Previous IARC Monographs on FormaldehydePrevious IARC Monographs on Formaldehyde

• Vol 29, 1981: inadequate evidence in humans, Vol 29, 1981: inadequate evidence in humans, sufficient evidence in animals (2B) sufficient evidence in animals (2B)

• Suppl1,1987: limited evidence in humans, Suppl1,1987: limited evidence in humans, sufficient evidence in animals, 2A sufficient evidence in animals, 2A

• Vol 62, 1994: limited evidence in humans, Vol 62, 1994: limited evidence in humans, sufficient evidence in animals, 2A sufficient evidence in animals, 2A

Reasons for re-evaluationReasons for re-evaluation

IARC IARC MonographsMonographs Advisory Group Advisory Group (Feb 2003) (Feb 2003) on on priorities for future evaluationspriorities for future evaluations

• New epidemiological studies available, New epidemiological studies available, two more will be finished soontwo more will be finished soon

• Complex mechanistic dataComplex mechanistic data

HighHigh priority for re-evaluation priority for re-evaluation

Overall Overall default evaluation default evaluation of carcinogenicityof carcinogenicity

Cancer in Cancer in experimental animalsexperimental animals

SufficientSufficient LimitedLimited InadequateInadequate

Cancer in Cancer in humanshumans

SufficientSufficient 11CarcinogenicCarcinogenic

11CarcinogenicCarcinogenic

11CarcinogenicCarcinogenic

LimitedLimited2A2A

ProbablyProbablycarcinogeniccarcinogenic

2B2BPossibly Possibly

carcinogeniccarcinogenic

2B2BPossibly Possibly

carcinogeniccarcinogenic

InadequateInadequate2B2B

PossiblyPossiblycarcinogeniccarcinogenic

33Not Not

classifiableclassifiable

33Not Not

classifiableclassifiable

The IARC MonographsThe IARC Monographs

Examination of all relevant information to assess the Examination of all relevant information to assess the weight of the evidence that certain exposures could weight of the evidence that certain exposures could alter the incidence of cancer in humans.alter the incidence of cancer in humans.

Do not include quantitative extrapolation of Do not include quantitative extrapolation of experimental data to humans.experimental data to humans.

Do not include recommendations regarding Do not include recommendations regarding regulation or legislation regulation or legislation ((responsibility of individual responsibility of individual governments governments && other international organizations. other international organizations.))

Nasopharyngeal Cancer (NPC) - INasopharyngeal Cancer (NPC) - I

US NCI Cohort among formaldehyde workersUS NCI Cohort among formaldehyde workers

• Statistically significant excess of deaths from NPC in Statistically significant excess of deaths from NPC in largest & most informative cohort study of industrial largest & most informative cohort study of industrial workersworkers (8 deaths, SMR 2.10, 95%CI 1.05-4.21)(8 deaths, SMR 2.10, 95%CI 1.05-4.21)

• Statistically significant exposure–response Statistically significant exposure–response relationships for peak (prelationships for peak (ptrendtrend < 0.001) and cumulative < 0.001) and cumulative exposureexposure (p(ptrendtrend = 0.03) = 0.03)

Nasopharyngeal Cancer (NPC) - IINasopharyngeal Cancer (NPC) - II

Other cohort studiesOther cohort studies

• Excess of deaths in largest US cohort of embalmersExcess of deaths in largest US cohort of embalmers (4 obs, 1.83 expected) (Hayes et al, 1990)(4 obs, 1.83 expected) (Hayes et al, 1990)

• Excess risk among workers using or manufacturing formaldehydeExcess risk among workers using or manufacturing formaldehyde in Denmark (SPIR 1.3, 95%CI 0.3-3.2) (Hansen and Olsen, 1995)in Denmark (SPIR 1.3, 95%CI 0.3-3.2) (Hansen and Olsen, 1995)

• 3 other cohort studies (US garment manufacturers, British 3 other cohort studies (US garment manufacturers, British chemical workers & US embalmers) with fewer cases than chemical workers & US embalmers) with fewer cases than expected, but low statistical power (Pinkerton et al, 2004; Coggon expected, but low statistical power (Pinkerton et al, 2004; Coggon et al, 2003; Walrath et al, 1983)et al, 2003; Walrath et al, 1983)

Nasopharyngeal Cancer (NPC) - IIINasopharyngeal Cancer (NPC) - III

Case-control studiesCase-control studies

• 5 of 7 case–control studies found increased risk for 5 of 7 case–control studies found increased risk for overall exposure to formaldehyde, or in higher overall exposure to formaldehyde, or in higher exposure categories, including one with statistically exposure categories, including one with statistically significantsignificant increase in riskincrease in risk

• 3 case–control studies (2 published since the last 3 case–control studies (2 published since the last Monograph) found higher risks in subjects with the Monograph) found higher risks in subjects with the highest probability, level or duration of exposurehighest probability, level or duration of exposure

Nasopharyngeal Cancer (NPC) - IVNasopharyngeal Cancer (NPC) - IV

Meta-analysisMeta-analysis

Most recent meta-analysis (Collins 1997)Most recent meta-analysis (Collins 1997)

• included some but not all of the above studies included some but not all of the above studies

• increased overall meta-relative risk for increased overall meta-relative risk for nasopharyngeal cancer (RR 1.3, 95%CI 1.2-1.5)nasopharyngeal cancer (RR 1.3, 95%CI 1.2-1.5)

Leukemia - ILeukemia - I

• Excess mortality observed consistently (Excess mortality observed consistently (66 of of 77 studies) studies) amongamong professional workers: embalmers, funeral parlour professional workers: embalmers, funeral parlour workers, pathologists and anatomists workers, pathologists and anatomists

• Recent meta-analysis for exposure to formaldehyde Recent meta-analysis for exposure to formaldehyde among professionals among professionals (Collins 2004)(Collins 2004)::increased overall summary relative risk estimates for increased overall summary relative risk estimates for embalmersembalmers (RR 1.6, 95%CI 1.2-2.0) (RR 1.6, 95%CI 1.2-2.0), and for pathologists, and for pathologists & & anatomists anatomists (RR 1.4, 95%CI 1.0-1.9)(RR 1.4, 95%CI 1.0-1.9)

• Predominantly myeloid Predominantly myeloid leukemialeukemia

Leukemia - IILeukemia - II

• Little direct evidence Little direct evidence

that these professionals have a higher incidence of that these professionals have a higher incidence of viral infections viral infections oor r

that viruses have a causal role in myeloid leukemia that viruses have a causal role in myeloid leukemia

• No material exposure to known leukemogensNo material exposure to known leukemogens

Leukemia - IIILeukemia - III• Statistically significant exposure–response relationship between Statistically significant exposure–response relationship between

peak exposures to formaldehyde and leukemia in cohort of peak exposures to formaldehyde and leukemia in cohort of U.S. U.S. industrial workers industrial workers (RR 2.5 95%CI 1.3-4.6) (Hauptmann et al, 2003)(RR 2.5 95%CI 1.3-4.6) (Hauptmann et al, 2003)

• Relationship particularly strong for myeloid leukemia (Relationship particularly strong for myeloid leukemia (RR 3.5 95%CI RR 3.5 95%CI 1.3-9.4)1.3-9.4)

• Mortality from leukemia less than expected when compared Mortality from leukemia less than expected when compared withwith general population as the referentgeneral population as the referent

• No exposure–response relationship with cumulative exposure - No exposure–response relationship with cumulative exposure - other metrics may be more relevant?other metrics may be more relevant?

Leukemia - IVLeukemia - IV

• Excess mortality from leukemia Excess mortality from leukemia among among entire cohort entire cohort of US garment workers (Pinkerton et al, 2004)of US garment workers (Pinkerton et al, 2004)

• Excess somewhat stronger for myeloid leukemia Excess somewhat stronger for myeloid leukemia

• Excess stronger among workers Excess stronger among workers with long duration of exposure and long follow-up, with long duration of exposure and long follow-up, who had been employed early in the study period who had been employed early in the study period when exposures to formaldehyde were believed to be when exposures to formaldehyde were believed to be the highest the highest

Leukemia - VLeukemia - V

• No No excess mortality among British industrial workers excess mortality among British industrial workers exposed to formaldehydeexposed to formaldehyde - - difficult to reconcile with difficult to reconcile with positive positive studiesstudies

• NoNo evaluation of peak exposures evaluation of peak exposures

• NoNo specific specific examinexamination ofation of myeloid leukemia myeloid leukemia

Sinonasal cancer - ISinonasal cancer - I• Pooled analysis of 12 occupational case–control Pooled analysis of 12 occupational case–control

investigationsinvestigations (Luce et al, 2002) (Luce et al, 2002)

• Increased risk for adenocarcinoma after adjustment for Increased risk for adenocarcinoma after adjustment for known occupational confounders known occupational confounders

• Increased risk among subjects never occupationally exposed Increased risk among subjects never occupationally exposed to wood or leather dustto wood or leather dust ((small number of exposed cases) small number of exposed cases)

• Dose–response trend for cumulative exposureDose–response trend for cumulative exposure

• Little evidence of association with SCCLittle evidence of association with SCC

Sinonasal cancer - IISinonasal cancer - II

• Increased risk of sinonasal cancer (particularly Increased risk of sinonasal cancer (particularly SCC) in one other case–control study & among SCC) in one other case–control study & among industrial workers in Denmark (proportionate industrial workers in Denmark (proportionate incidence study) (Olsen et al, 1986; Hansen et incidence study) (Olsen et al, 1986; Hansen et al, 1995)al, 1995)

• No excess of sinonasal cancer in recently No excess of sinonasal cancer in recently updated industrial cohort studiesupdated industrial cohort studies

Sinonasal cancer - IIISinonasal cancer - III

• Most studies have not distinguished tumours arising Most studies have not distinguished tumours arising in the nose from those developing in the nasal in the nose from those developing in the nasal sinuses - effect on the risk of nasal cancer would be sinuses - effect on the risk of nasal cancer would be diluted if there were no corresponding effect on the diluted if there were no corresponding effect on the risk of cancer in the sinusesrisk of cancer in the sinuses

• Discrepancy between results of case–control and Discrepancy between results of case–control and cohort studies might also reflect residual confounding cohort studies might also reflect residual confounding by wood dust in the formerby wood dust in the former

Overall evaluationOverall evaluation

• Formaldehyde Formaldehyde is carcinogenic to humans, Group 1is carcinogenic to humans, Group 1

• Sufficient evidence in humans that formaldehyde Sufficient evidence in humans that formaldehyde causes nasopharyngeal cancer causes nasopharyngeal cancer

• SStrong but not sufficient evidence for a causal trong but not sufficient evidence for a causal association between leukemia and occupational association between leukemia and occupational exposure to formaldehydeexposure to formaldehyde

• Limited evidence in humans that formaldehyde causes Limited evidence in humans that formaldehyde causes sinonasal cancer. sinonasal cancer.

PublicationsPublications• VJ Cogliano, Y Grosse, RA Baan, K Straif, MB Secretan, F El Ghissassi. Advice on VJ Cogliano, Y Grosse, RA Baan, K Straif, MB Secretan, F El Ghissassi. Advice on

formaldehyde and glycol ethers. formaldehyde and glycol ethers. The Lancet Oncology 2004, 5:528The Lancet Oncology 2004, 5:528• VJ Cogliano, Y Grosse, RA Baan, K Straif, MB Secretan, F El Ghissassi, and the 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 Working Group for Volume 88*. Meeting report: summary of IARC Monographs on formaldehyde, 2-butoxyethanol and 1-tert-butoxy-2-propanol. Environ Health formaldehyde, 2-butoxyethanol and 1-tert-butoxy-2-propanol. Environ Health Perspect 2005, 113: 1205 –8Perspect 2005, 113: 1205 –8

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

Summary of relevant data for evaluating Summary of relevant data for evaluating carcinogenicitycarcinogenicity

11. Exposure information. Exposure information

22. Reports of carcinogenicity in humans. Reports of carcinogenicity in humans

33. Reports of carcinogenicity in experimental . Reports of carcinogenicity in experimental animalsanimals

44. Other data relevant to the evaluation of . Other data relevant to the evaluation of carcinogenicity and its mechanismscarcinogenicity and its mechanisms

CarcinogenicityCarcinogenicity in humans in humans

Sufficient evidence of carcinogenicitySufficient 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

Other data relevant to an evaluation of Other data relevant to an evaluation of carcinogenicity and its mechanismscarcinogenicity and its mechanisms

• Evidence of genotoxicity (structural changes at the Evidence of genotoxicity (structural changes at the gene level)gene level)

• Evidence of effects on relevant gene expression Evidence of effects on relevant gene expression (functional changes at the intracellular level(functional changes at the intracellular level

• Evidence of relevant effects on cell behavior Evidence of relevant effects on cell behavior (morphologic or behavioral changes at the cellular or (morphologic or behavioral changes at the cellular or tissue level); tissue level);

• Evidence from dose and time relationships of Evidence from dose and time relationships of carcinogenic effects and interactions between agentscarcinogenic effects and interactions between agents