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Minisymposium 1

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Formaldehyde and cancer: current evidence and future perspectives

M1.1 EPIDEMIOLOGICAL STUDIES OF FORMALDEHYDE AND CANCER: RECENT RESULTS AND THEIR INTERPRETATION

M. Hauptmann.National Cancer Institute, NIH/DHHS, Bethesda, Maryland, USA

Formaldehyde is a chemical of enormous economic impact, with a worldwide production of over 12 million tons in 1992. It is used in the production of resins, moulding compounds, photographic film, decorative laminates and plywood, and as a bactericide and tissue preservative. Approximately 1.5 million workers are exposed to formaldehyde in the USA, and about 1 million in the European Union. Formaldehyde carcinogenicity has been studied extensively over the last 30 years and it is carcinogenic in animal bioassays. The human data have been less clear. Recently, results from three updated cohort studies of industrial workers have been published in 2003 and 2004, and this summer the International Agency for Research on Cancer re-reviewed formaldehyde and changed its evaluation from probably carcinogenic (class 2A) to carcinogenic for humans (class 1) based on nasopharyngeal cancer, a very rare cancer. Several earlier studies of embalmers and pathologists and two of the three recently updated cohort studies suggest a possible association between formaldehyde exposure and leukaemia. The potential impact of these findings, particularly for risk assessment, is a subject of controversial discussion in the scientific community. This presentation will give an overview of the major epidemiological studies and address some of the challenges in interpreting the results. It will set the stage for the subsequent presentations of diverse areas of research into formaldehyde carcinogenicity and provide the epidemiological basis for the discussion.

M1.2 AN UPDATED META-ANALYSIS OF FORMALDEHYDE AND RESPIRATORY CANCER

D. M. McElvenny1,2, B. G. Armstrong1.1Public and Environmental Health Research Unit, London School of Hygiene and Tropical Medicine, London, UK; 2Epidemiology and Medical Statistics Unit, Health and Safety Executive, Merseyside, UK

Introduction: The recent publication of update of three large cohorts of workers exposed to formaldehyde provided the motivation for an up to date assessment of the respiratory carcinogenicity of formaldehyde.

Methods: A literature search was undertaken to identify all the additionally relevant epidemiological studies. Earlier reports of studies were excluded. Standard meta-analytical techniques were applied to the respiratory cancer results from the individual studies. The results presented here are those restricted to cohort studies, including nested case–control studies, of industrial and professional workers such as pathologists, anatomists, and embalmers.

Results: Twenty cohort studies were identified with results that could be incorporated into a meta-analysis. The mean relative risks are set out in table 1.

Table 1

 Risk of particular types of cancer in workers

Conclusions: The 2696 lung cancers, over half of which are from the three recently updated cohorts, provided weak evidence for a lung cancer risk from occupational exposure to formaldehyde for industrial workers only. The findings for nasal cancer (five cases) and nasopharyngeal cancer (13 cases) are based on small numbers (because these cancers are often unreported), so must be interpreted with caution. Despite this, the evidence for an association with for nasopharyngeal cancer is suggestive for both occupational groups, and is being investigated in more detail.

M1.3 CELLULAR MECHANISMS UNDERLYING TOXICITY AND CANCER RISK OF FORMALDEHYDE EXPOSURE

R. C. Grafström.Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden

In vitro methods have been extensively utilised to study mechanisms of formaldehyde toxicity. Both cytotoxic and genotoxic effects are induced in dose dependent manners in cell cultures of human origin. Alterations in molecular variables include colony forming efficiency, clonal growth rate, membrane integrity, vital dye accumulation, cytosolic free calcium ion levels, low molecular weight and protein thiols, and DNA integrity/structure (formation of DNA adducts, DNA single strand breaks and interstrand crosslinks, DNA–protein crosslinks, 6-thioguanine resistance mutations, and the induction of aberrant differentiated and apoptotic states and cell transformation). Formaldehyde also influences various enzymatic activities, including for DNA repair. Formaldehyde synergistically increases the cytotoxic and genotoxic effects of other agents, including N-nitroso compounds and ionising radiation. Assessed using identical model systems and exposure conditions, formaldehyde exhibited a unique spectrum of cytopathological activity that differs from that of two other aldehydes, acetaldehyde and acrolein. The major defence against formaldehyde toxicity occurs through spontaneous reactions with thiols and oxidation through alcohol dehydrogenase 3 (ADH3). This enzyme also catalyses reduction of the conjugate of glutathione and nitric oxide (GSNO), implying the possibility that formaldehyde exposure may indirectly involve influences of oxidants. The various cellular effects of formaldehyde agree with its classification as a cancer inducing agent. Possible induction of cancer distant from sites exposed by inhalation suggests a need for studies of indirect toxicity mechanisms of formaldehyde. Effects related to metabolism of formaldehyde and the potential for synergistic actions with other toxic and mutagenic agents may be particularly relevant.

M1.4 MECHANISTIC CONSTRAINTS ON SITES OF FORMALDEHYDE INDUCED CANCER

R. B. Conolly, J. S. Kimbell.CIIT Centers for Health Research, Research Triangle Park, NC, USA

Formaldehyde is a reactive, water soluble small molecule. In combination with the breathing rate and the shapes of the respiratory tract airways, these physicochemical properties determine the spatial pattern of flux of formaldehyde from inhaled air into tissues lining the respiratory tract. These factors together determine the specific cell populations that receive the highest delivered dose. Chronic inhalation of formaldehyde by rats and mice causes formation of DNA–protein cross links, cytotoxicity, adaptive changes, preneoplastic lesions, and tumours. These effects occur in the anterior nose, which is the primary site of formaldehyde uptake. The incidence and severity of the lesions falls off sharply with an anterior to posterior gradient. We have developed three dimensional computer reconstructions of the nasal airways of rats, rhesus monkeys, and humans, and used these models to simulate airflow and tissue uptake of inhaled formaldehyde. Computer predictions of high anterior dose in rats and rhesus monkeys are consistent with the sites of lesions seen experimentally, and the overall nasal uptake in rats is consistent with experimental measurements of formaldehyde uptake in these species. Taken together, these experimental and computational studies identify a close correlation between the tissue dose of formaldehyde and its carcinogenic effects in rodents. In the human nose, the nasopharyngeal region has been identified in epidemiological studies as a target site for formaldehyde induced cancer. The nasopharynx, however, is posterior to the expected site of highest delivered dose in the human nose. The ratio of delivered dose in the anterior nose to that in the nasopharynx is predicted to vary from about twofold to more than tenfold, depending on the breathing rate. Moreover, nonlinearities in the tissue dose–adverse response relationship are predicted to magnify the differences in tissue dose with respect to tumour formation. The association of nasopharyngeal cancer with formaldehyde inhalation is thus not consistent with experience from either laboratory experiments or from computational modelling. Possible explanations for this discrepancy include a special sensitivity of the nasopharyngeal region in humans, perhaps associated with the presence of Epstein-Barr virus, or confounding exposures such as cigarette smoke.

M1.5 SYNTHESIS

D. Coggon.MRC Environmental Epidemiology Unit, University of Southampton, UK

This presentation will consider the implications for risk assessment of the current balance of evidence on human carcinogenicity of formaldehyde. It will highlight a number of contentious issues for discussion by the workshop including: (a) the absence of excess nasopharyngeal cancer in some large and heavily exposed industrial cohorts when other cohort and case–control studies have indicated positive associations; (b) the paucity of epidemiological evidence for a hazard of nasal cancer when the nose is the organ that incurs the highest exposures to formaldehyde and has been a site of cancer in experimental studies; (c) the inconsistency of epidemiological findings on leukaemia and the dubious mechanistic support for a hazard of this type of cancer; and (d) the evidence for and against a genotoxic mechanism of carcinogenicity. One aim of the discussion that follows should be to identify further epidemiological research that might help to resolve any critical outstanding uncertainties in risk assessment.

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