Previous IARC Monographs on Formaldehyde

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Previous IARC Monographs on Formaldehyde

• Vol 29, 1981 inadequate evidence in humans,
  sufficient evidence in animals
  (2B)
• Suppl1,1987 limited evidence in humans,
  sufficient evidence in animals, 2A
• Vol 62, 1994 limited evidence in humans,
  sufficient evidence in animals, 2A

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Reasons for re-evaluation

• IARC Monographs Advisory Group (Feb 2003) on
  priorities for future evaluations
• New epidemiological studies available, two more
  will be finished soon
• Complex mechanistic data
• High priority for re-evaluation

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Overall default evaluation of carcinogenicity
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The IARC Monographs

• Examination of all relevant information to assess
  the weight of the evidence that certain exposures
  could alter the incidence of cancer in humans.
• Do not include quantitative extrapolation of
  experimental data to humans.
• Do not include recommendations regarding
  regulation or legislation (responsibility of
  individual governments other international
  organizations.)

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Nasopharyngeal Cancer (NPC) - I

• US NCI Cohort among formaldehyde workers
• Statistically significant excess of deaths from
  NPC in largest most informative cohort study of
  industrial workers (8 deaths, SMR 2.10, 95CI
  1.05-4.21)
• Statistically significant exposureresponse
  relationships for peak (ptrend lt 0.001) and
  cumulative exposure (ptrend 0.03)

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Nasopharyngeal Cancer (NPC) - II

• Other cohort studies
• Excess of deaths in largest US cohort of
  embalmers (4 obs, 1.83 expected) (Hayes et al,
  1990)
• Excess risk among workers using or manufacturing
  formaldehyde in Denmark (SPIR 1.3, 95CI 0.3-3.2)
  (Hansen and Olsen, 1995)
• 3 other cohort studies (US garment manufacturers,
  British chemical workers US embalmers) with
  fewer cases than expected, but low statistical
  power (Pinkerton et al, 2004 Coggon et al, 2003
  Walrath et al, 1983)

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Nasopharyngeal Cancer (NPC) - III

• Case-control studies
• 5 of 7 casecontrol studies found increased risk
  for overall exposure to formaldehyde, or in
  higher exposure categories, including one with
  statistically significant increase in risk
• 3 casecontrol studies (2 published since the
  last Monograph) found higher risks in subjects
  with the highest probability, level or duration
  of exposure

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Nasopharyngeal Cancer (NPC) - IV

• Meta-analysis
• Most recent meta-analysis (Collins 1997)
• included some but not all of the above studies
• increased overall meta-relative risk for
  nasopharyngeal cancer (RR 1.3, 95CI 1.2-1.5)

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Leukemia - I

• Excess mortality observed consistently (6 of 7
  studies) among professional workers embalmers,
  funeral parlour workers, pathologists and
  anatomists
• Recent meta-analysis for exposure to formaldehyde
  among professionals (Collins 2004)increased
  overall summary relative risk estimates for
  embalmers (RR 1.6, 95CI 1.2-2.0), and for
  pathologists anatomists (RR 1.4, 95CI 1.0-1.9)
• Predominantly myeloid leukemia

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Leukemia - II

• Little direct evidence that these professionals
  have a higher incidence of viral infections or
  that viruses have a causal role in myeloid
  leukemia
• No material exposure to known leukemogens

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Leukemia - III

• Statistically significant exposureresponse
  relationship between peak exposures to
  formaldehyde and leukemia in cohort of U.S.
  industrial workers (RR 2.5 95CI 1.3-4.6)
  (Hauptmann et al, 2003)
• Relationship particularly strong for myeloid
  leukemia (RR 3.5 95CI 1.3-9.4)
• Mortality from leukemia less than expected when
  compared with general population as the referent
• No exposureresponse relationship with cumulative
  exposure - other metrics may be more relevant?

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Leukemia - IV

• Excess mortality from leukemia among entire
  cohort of US garment workers (Pinkerton et al,
  2004)
• Excess somewhat stronger for myeloid leukemia
• Excess stronger among workers with long duration
  of exposure and long follow-up, who had been
  employed early in the study period when exposures
  to formaldehyde were believed to be the highest

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Leukemia - V

• No excess mortality among British industrial
  workers exposed to formaldehyde - difficult to
  reconcile with positive studies
• No evaluation of peak exposures
• No specific examination of myeloid leukemia

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Sinonasal cancer - I

• Pooled analysis of 12 occupational casecontrol
  investigations (Luce et al, 2002)
• Increased risk for adenocarcinoma after
  adjustment for known occupational confounders
• Increased risk among subjects never
  occupationally exposed to wood or leather dust
  (small number of exposed cases)
• Doseresponse trend for cumulative exposure
• Little evidence of association with SCC

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Sinonasal cancer - II

• Increased risk of sinonasal cancer (particularly
  SCC) in one other casecontrol study among
  industrial workers in Denmark (proportionate
  incidence study) (Olsen et al, 1986 Hansen et
  al, 1995)
• No excess of sinonasal cancer in recently updated
  industrial cohort studies

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Sinonasal cancer - III

• Most studies have not distinguished tumours
  arising in the nose from those developing in the
  nasal sinuses - effect on the risk of nasal
  cancer would be diluted if there were no
  corresponding effect on the risk of cancer in the
  sinuses
• Discrepancy between results of casecontrol and
  cohort studies might also reflect residual
  confounding by wood dust in the former

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Overall evaluation

• Formaldehyde is carcinogenic to humans, Group 1
• Sufficient evidence in humans that formaldehyde
  causes nasopharyngeal cancer
• Strong but not sufficient evidence for a causal
  association between leukemia and occupational
  exposure to formaldehyde
• Limited evidence in humans that formaldehyde
  causes sinonasal cancer.

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Publications

• VJ Cogliano, Y Grosse, RA Baan, K Straif, MB
  Secretan, F El Ghissassi. Advice on formaldehyde
  and glycol ethers. The Lancet Oncology 2004,
  5528
• VJ Cogliano, Y Grosse, RA Baan, K Straif, MB
  Secretan, F El Ghissassi, and the Working Group
  for Volume 88. Meeting report summary of IARC
  Monographs on formaldehyde, 2-butoxyethanol and
  1-tert-butoxy-2-propanol. Environ Health Perspect
  2005, 113 1205 8

Ulrich Andrae, Germany, Sherwood Burge, UK.
Rajendra Chhabra, USA, John Cocker, UK, David
Coggon, UK, Rory Conolly, USA, Paul Demers,
Canada, David Eastmond, USA, Elaine Faustman,
USA, Victor Feron, The Netherlands, Michel Gérin,
Canada (Chair) Marcel Goldberg, France, Bernard
Goldstein, USA, Roland Grafström, Sweden, Johnni
Hansen, Denmark, Michael Hauptmann, USA, Kathy
Hughes, Canada, Ted Junghans, USA, Dan Krewski,
Canada, Steve Olin, USA, Martine Reynier, France,
Judith Shaham, Israel, Morando Soffritti, Italy,
Leslie Stayner, USA, Patricia Stewart, USA,
Douglas Wolf, USA,
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Summary of relevant data for evaluating
carcinogenicity

• 1. Exposure information
• 2. Reports of carcinogenicity in humans
• 3. Reports of carcinogenicity in experimental
  animals
• 4. Other data relevant to the evaluation of
  carcinogenicity and its mechanisms

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Carcinogenicity in humans

• Sufficient evidence of carcinogenicity
• The Working Group considers that a causal
  relationship has been established between
  exposure to the agent, mixture, or exposure
  circumstance and human cancer.
• A positive relationship has been observed between
  the exposure and cancer in studies in which
  chance, bias and confounding could be ruled out
  with reasonable confidence

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Other data relevant to an evaluation of
carcinogenicity and its mechanisms

• Evidence of genotoxicity (structural changes at
  the gene level)
• Evidence of effects on relevant gene expression
  (functional changes at the intracellular level
• Evidence of relevant effects on cell behavior
  (morphologic or behavioral changes at the
  cellular or tissue level)
• Evidence from dose and time relationships of
  carcinogenic effects and interactions between
  agents