Development of carcinogenicity classifications and evaluations: the case of formaldehyde.

In this paper carcinogenicity classification and evaluations case of formaldehyde made by national and international agencies and organizations (such as European Union, International Agency for Research on Cancer, World Health Organization) both in occupational (such as American Conference of Government Industrial Hygienists, National Institute of Occupational Safety and Health and Occupational Health and Safety Administration) and non occupational environment (such as United States Environmental Protection Agency) are proposed. The differences in the database and consequently in the conclusion are described in a short historical review since formaldehyde was considered for the first time as regard as health effects.

Human respiratory tract cancer risks of inhaled formaldehyde: dose-response predictions derived from biologically-motivated computational modeling of a combined rodent and human dataset.

Formaldehyde inhalation at 6 ppm and above causes nasal squamous cell carcinoma (SCC) in F344 rats. The quantitative implications of the rat tumors for human cancer risk are of interest, since epidemiological studies have provided only equivocal evidence that formaldehyde is a human carcinogen. Conolly et al. (Toxicol. Sci. 75, 432-447, 2003) analyzed the rat tumor dose-response assuming that both DNA-reactive and cytotoxic effects of formaldehyde contribute to SCC development. The key elements of their approach were: (1) use of a three-dimensional computer reconstruction of the rat nasal passages and computational fluid dynamics (CFD) modeling to predict regional dosimetry of formaldehyde; (2) association of the flux of formaldehyde into the nasal mucosa, as predicted by the CFD model, with formation of DNA-protein cross-links (DPX) and with cytolethality/regenerative cellular proliferation (CRCP); and (3) use of a two-stage clonal growth model to link DPX and CRCP with tumor formation. With this structure, the prediction of the tumor dose response was extremely sensitive to cell kinetics. The raw dose-response data for CRCP are J-shaped, and use of these data led to a predicted J-shaped dose response for tumors, notwithstanding a concurrent low-dose-linear, directly mutagenic effect of formaldehyde mediated by DPX. In the present work the modeling approach used by Conolly et al. (ibid.) was extended to humans. Regional dosimetry predictions for the entire respiratory tract were obtained by merging a three-dimensional CFD model for the human nose with a one-dimensional typical path model for the lower respiratory tract. In other respects, the human model was structurally identical to the rat model. The predicted human dose response for DPX was obtained by scale-up of a computational model for DPX calibrated against rat and rhesus monkey data. The rat dose response for CRCP was used "as is" for the human model, since no preferable alternative was identified. Three sets of baseline parameter values for the human clonal growth model were obtained through separate calibrations against respiratory tract cancer incidence data for nonsmokers, smokers, and a mixed population of nonsmokers and smokers, respectively. Additional risks of respiratory tract cancer were predicted to be negative up to about one ppm for all three cases when the raw CRCP data from the rat were used. When a hockey-stick-shaped model was fit to the rat CRCP data and used in place of the raw data, positive maximum likelihood estimates (MLE) of additional risk were obtained. These MLE estimates were lower, for some comparisons by as much as 1,000-fold, than MLE estimates from previous cancer dose-response assessments for formaldehyde. Breathing rate variations associated with different physical activity levels did not make large changes in predicted additional risks. In summary, this analysis of the human implications of the rat SCC data indicates that (1) cancer risks associated with inhaled formaldehyde are de minimis (10(-6) or less) at relevant human exposure levels, and (2) protection from the noncancer effects of formaldehyde should be sufficient to protect from its potential carcinogenic effects.

Mis-specified and non-robust mortality risk models for nasopharyngeal cancer in the National Cancer Institute formaldehyde worker cohort study.

An IARC (International Agency for Research on Cancer) working group categorized formaldehyde as a human carcinogen (Group 1) in 2004. A major component of the epidemiologic evidence evaluated by IARC to reach this decision was the analysis published by Hauptmann et al. [Hauptmann, M., Lubin, J. H., Stewart, P. A., Hayes, R. B., Blair, A. 2004. Mortality from solid cancers among workers in formaldehyde industries. Am. J. Epidemiol. 159, 1117-1130.] of the National Cancer Institute (NCI) historical cohort comprising industrial workers exposed to formaldehyde in 10 U.S. plants. The NCI authors emphasized the relationship found between highest formaldehyde peak exposure and death from nasopharyngeal cancer (NPC). We performed two additional types of re-analyses of the NCI cohort data with focus on peak exposure and NPC mortality. The analyses were aimed at (1) investigating whether the model specification chosen by Hauptmann et al. (2004) was appropriate (interaction assessment) and (2) exploring the degree of instability of the risk estimates for NPC in relation to highest peak exposure (sensitivity analysis). Hauptmann et al. (2004) failed to account for an important interaction structure between plant group and the exposure variable that prohibits a generalization of formaldehyde effects within the NCI cohort and, in particular, beyond the NCI cohort. In addition, our sensitivity analysis demonstrates considerable uncertainties in the risk estimates and points convincingly to instability problems particularly related to Plant 1. Even a simple sensitivity model taking only one additional death into account produced a variation of the risk estimates beyond the instability conveyed by standard confidence intervals. The results of our current reanalysis of the NCI study do not support NCI's suggestion of a causal association with formaldehyde exposure and nasopharyngeal cancer. The decision by the IARC working group to reclassify formaldehyde as a Group 1 substance was clearly premature considering: (1) the missing evidence of an NPC excess from the large British and NIOSH cohort studies; (2) the absence of an association with formaldehyde and NPC in the independent and expanded study of Plant 1; and (3) the mis-specified and non-robust internal analysis of the NCI cohort study brought to light in our current re-analysis. Thus, the 2004 IARC decision to reclassify formaldehyde as a Group 1 substance should be reconsidered.

Transcriptomic analysis of F344 rat nasal epithelium suggests that the lack of carcinogenic response to glutaraldehyde is due to its greater toxicity compared to formaldehyde.

Formaldehyde is cytotoxic and carcinogenic to the rat nasal respiratory epithelium inducing tumors after 12 months. Glutaraldehyde is also cytotoxic but is not carcinogenic to nasal epithelium even after 24 months. Both aldehydes induce similar acute and subchronic histopathology that is characterized by inflammation, hyperplasia, and squamous metaplasia. Because early aldehyde-induced lesions are microscopically similar, we investigated whether transcriptional patterns using cDNA technology could explain the different cancer outcomes. Treatments included 1-, 5-, or 28-day exposure by nasal instillation of formaldehyde solution (400 mM) or glutaraldehyde solution (20 mM). Animals were euthanized and the nasal respiratory epithelium removed for gene expression analysis and a subset of rats treated for 28 days was processed for microscopic examination. RNA was isolated and processed for expression assessment using Clontech Atlas Toxicology II Arrays. Both aldehydes induced hyperplasia, squamous metaplasia, and inflammatory infiltrates with scattered apoptotic bodies in the epithelium covering luminal surfaces of the nasoturbinate, maxilloturbinate, and nasal septum. A subset of 80 genes that were the most variant between the treated and control included the functional categories of DNA repair and apoptosis. Hierarchical clustering discriminated chemical treatment effects after 5 days of exposure, with 6 clusters of genes distinguishing formaldehyde from glutaraldehyde. These data suggest that although both aldehydes induced similar short-term cellular phenotypes, gene expression could distinguish glutaraldehyde from formaldehyde. The gene expression patterns suggest that glutaraldehyde's lack of carcinogenicity may be due to its greater toxicity from lack of DNA-repair, greater mitochondrial damage, and increased apoptosis.