Review of the Formaldehyde Assessment in the National Toxicology Program 12th Report on Carcinogens (2014) / Chapter Skim
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3 Independent Assessment of Formaldehyde
3 Independent Assessment of Formaldehyde
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From page 66... ...
After identifying the relevant body of literature up to November 8, 2013, the committee reviewed the primary data and applied the RoC listing criteria to human, experimental animal, and mechanistic studies. This chapter begins with a section on cancer studies in humans, which is followed by a section on cancer studies in experimental animals.
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From page 67... ...
to an unusual degree with regard to incidence, site, or type of tumor, or age at onset." "There is less than sufficient evidence of carcinogenicity in humans or laboratory animals; however, the agent, substance, or mixture belongs to a welldefined, structurally related class of substances whose members are listed in a previous Report on Carcinogens as either known to be a human carcinogen or reasonably anticipated to be a human carcinogen, or there is convincing relevant information that the agent acts through mechanisms indicating it would likely cause cancer in humans." A substance can be listed as "known to be a human carcinogen" if "there is sufficient evidence of carcinogenicity from studies in humans, which indicates a causal relationship between exposure to the agent, substance, or mixture, and human cancer." The RoC listing criteria are clear about the information needed to fulfill the criteria of sufficient evidence in experimental animals (see the section "Cancer Studies in Experimental Animals")
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From page 68... ...
Table 3-2 provides information about all the epidemiologic studies that the committee considered, including a description of the studies, a description of the exposure assessments used in each study, comments on strengths and limitations of the studies, and the committee's determination of study quality (strong, moderately strong, or weak)
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From page 69... ...
For example, several strong case–control studies of licensed embalmers had no exposure assessments, but because the case definition required work as a licensed embalmer and that occupation has well-defined rules for practice (which define the exposure situation) , the resulting studies were considered to be strong or moderately strong.
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From page 70... ...
, total strong sinonasal cancer = 0 cases, history available for each study subject; duration of exposure was short Iron foundry workers lymphohematopoietic cancer = 15, extensive data from industrial-hygienist (≤17 years) from Michigan, USA leukemia = 5 cases; 3,929 workers with sampling, technical data from plant, potential exposure to formaldehyde for walk-through surveys, and job and task Although the study had a ≥6 months during 1960–1987; 83,064 descriptions; information assessed by an high-discrimination quantitative person-years for exposed and 40,719 industrial hygienist and assigned to high exposure assessment and the person-years for controls; a smoking- (median 1.5 ppm)
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From page 71... ...
2001 Population-based leukemia case–control; Low-discrimination semiquantitative There were 513 incident cases, Weak outcome: incidence; 513 incident cases; exposure assessment for formaldehyde; but the study was judged to be General population ascertainment period: Iowa 1981–1983, broad job categories and industries; weak for assessing in Iowa and Minnesota 1980–1982 potential formaldehyde exposure was formaldehyde because the Minnesota categorized on a 4-point scale; likely number of cases with high high misclassification exposure (n = 3) was small, misclassification likely Checkoway et Case–cohort nested within cohort of Low-discrimination qualitative exposure Few workers exposed to Weak al.
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From page 72... ...
; "high" exposure category was estimated to be over 2 ppm; no peak exposures identified; authors noted that there was some exposure to paraformaldehyde Dell and Teta 1995 Cohort = 5,932; outcome: mortality; Low-discrimination qualitative exposure Small study size had little power Weak nasopharyngeal cancer = 0 deaths, assessment; company job histories to detect risk of rare tumors Workers employed in sinonasal cancer = 0 deaths, collected; duration of employment used a Union Caribide lymphohematopoietic cancer = 28 deaths, as a surrogate for cumulative exposure; Few workers exposed to plastics leukemia and aleukemia = 12 deaths; some analysis of work department made formaldehyde manufacturing plant workers employed in 1946–1967; but limited by missing work data Limited exposure information in New Jersey followup through 1988; 5,932 males in the cohort (111 exposed to formaldehyde) Multiple concomitant exposures (raw materials used in the manufacturing process included asbestos [usually chrysotile]
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From page 73... ...
1991 Cohort = 4,512 men; outcome: Low-discrimination qualitative exposure Small study size had little power Weak mortality; nasopharyngeal cancer = 0 assessment on the basis of job title to detect risk of rare tumor UK pathologists cases, sinonasal cancer = 0 cases, (formaldehyde exposure was assumed leukemia = 4 cases; men identified in from cadavers) ; no discussion of High likelihood of 1973 Royal College of Pathologists exposure conditions was presented misclassification on exposure to membership list; followup period: 1974– formaldehyde; pathologists have 1987 less likelihood of exposures than embalmers Hansen and Olsen Cohort = 91,182 men with cancer, 2,041 Moderate-discrimination Study limited by lack of data on Weak 1995, 1996 men with longest work experience of semiquantitative exposure assessment; intensity of exposures and ≥10 years before the date of diagnosis of potentially exposed cases were identified internal plant operations Danish data-linkage cancer, 265 companies where as those with ≥10 years of blue-collar study identifying formaldehyde was used; outcome: work experience in formaldehyde-using Cohort had no or few cases of incident cancers in incidence; nasopharyngeal cancer = 4 companies; formaldehyde exposures some types of cancers, and this companies in which cases, cancer of the nasal cavity = 13 were ranked as low (white-collar jobs)
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From page 74... ...
1986 Case–control; outcome: incidence; Moderate-discrimination qualitative Study limited by disagreement Moderately histological types of sinonasal cancer = exposure assessment; work history between exposure assignments strong General population 116 cases; cancer diagnosed in 1978– collected by interview included all jobs of 2 independent raters, but the in the Netherlands 1981; cases drawn from all six major held for 6 months or more; all jobs were association of formaldehyde hospitals for treatment of head and neck classified by industrial hygienists exposure and nasal cancer was tumors according to level and probability of similar for each rater formaldehyde exposure on 10-point scale; agreement between two raters was poor For sinonasal cancer, the study for adjacent scores, and this resulted in suggests an association between high potential for misclassification in formaldehyde and squamous adjacent categories, which was rare for cell carcinoma, not high to low or low to high adenocarcinoma Hildesheim et Population case–control; outcome: Moderate-discrimination semiquantitative Considerable overlap in wood Moderately al. 2001 incidence; nasopharyngeal cancer = 375 exposure assessment; occupational history dust, formaldehyde exposures; strong cases; newly diagnosed, histologically data obtained by interview; exposures authors were concerned about General population confirmed nasopharyngeal cancer in were assigned to broad occupation codes greater misclassification for in Taiwan people younger than 75 years old who on basis of professional judgment of study formaldehyde than wood-dust were residents of Taipei City or County industrial hygienist; exposures were assignments for ≥6 months; cases identified at 2 classified from 0 (not exposed)
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From page 75... ...
2006 Cohort = 267,400; outcome: incidence; Low-discrimination qualitative exposure Limited use of formaldehyde in Weak nasopharyngeal cancer = 67 cases, assessment for formaldehyde, which was textile operations; very few Chinese female sinonasal cancer = 10 cases; cases secondary to a primary evaluation of workers exposed (only 10 cases textile workers in identified in 1989–1998; 267,400 female textile production exposures; complete exposed to formaldehyde and 526 factories in textile workers drawn in 1925–1958 occupational history in textile industry none of the NPC cases were Shanghai was collected; factory profile form was classified as exposed) used by industrial hygienists in Shanghai to record for each factory production processes, types of workshops, and historical measurements of hazardous exposures since establishment of factory Luce et al.
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From page 76... ...
diagnosed in 1968–1990; pooled data coded uniformly; quantitative exposure from 12 case–control studies in seven data used to construct job–exposure countries matrix; hygienists assigned probabilities and intensities of formaldehyde exposure; cumulative exposure was principal summary measure of exposure; 192 cases with medium or high exposure to formaldehyde; authors evaluated effects of coexposures to wood dust Luo et al. 2011 Ecologic study; outcome: SEER lung- Low-discrimination semiquantitative Caution needed in interpreting Weak cancer incidence rates by county; data on exposure assessment; county-level ecologic associations as causal; General population age-adjusted lung-cancer incidence rates quantitative data on industrial release of high potential for in 13 US regions in 1992–2007; county-level correlation formaldehyde as proxy for general misclassification in large covered by SEER of Toxics Release Inventory data on population exposure in the county counties registries formaldehyde release with lung-cancer incidence rate from the SEER database Mahboubi et Population-based case–control study; Moderate-discrimination Large, well-conducted study; Moderately al.
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From page 77... ...
(2004) without substantial peaks or intermittent to detect an effect for rare exposures cancers, such as nasopharyngeal cancer, sinonasal cancer Olsen and Case–control; outcome: incidence; Moderate-discrimination qualitative Only small numbers of cases Moderately Asnaes 1986 nasopharyngeal cancer = 293 cases, exposure assessment; employment ever exposed to formaldehyde strong sinonasal cancer = 466 cases; histories obtained from national pension, (13 cases of squamous-cell General population histologically confirmed cancer cases in population registries and exposure carcinoma; 17 cases of in Denmark 1970–1982; male cases and controls classified by job description, industry; adenocarcinoma ever exposed selected from Danish Cancer Registry each job rated by industrial hygienist as to formaldehyde)
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From page 78... ...
1993 Nested case–control; outcome: Moderate-discrimination qualitative Medium formaldehyde Moderately incidence; Hodgkin disease = 4, non- exposure assessment; methodology exposures likely, but study strong Finnish wood- Hodgkin lymphoma = 8, leukemia = 12; assigned exposure based on personal limited by small number of cases industry workers cancer cases diagnosed in 1957–1982 work histories and a job–exposure matrix that identified formaldehyde exposure; no average exposure intensity was provided Pesch et al. 2008 Industry-based case–control; outcome: Low-discrimination qualitative exposure Strong study of wood-dust Weak incidence; histologically confirmed assessment of formaldehyde; association with sinonasal German wood sinonasal cancer = 86 cases; recognized questionnaire collection of occupational cancer, but weak assessment of industry occupational disease diagnosed in 1994– history with additional data on wood- formaldehyde exposure 2003; cases identified from workers related exposures and chemical insured by Holz-BG insurance company treatments, including formaldehyde; Substantial exposure personal sampling for wood-dust exposure misclassification was likely in 1992–2002; expert industrial hygienists estimated wood-dust exposure to identify missing information and trends; crude assessment of formaldehyde exposures (yes/no)
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From page 79... ...
2012 Cohort = 1.2 million working Finnish Moderate-discrimination quantitative Few cases with formaldehyde Moderately men; outcome: incidence; nose = 292 exposure assessment; occupation in 1970 exposure for three of the four strong Finnish general cases, nasal squamous-cell carcinoma = linked to job–exposure matrix to types of cancer investigated (17 population 167 cases, nasopharyngeal cancer = 149 estimate wood-dust exposure, cases of cancer of the nose, 9 cases; followup period: 1971–1995; data formaldehyde exposure, coexposures to cases of nasal squamous-cell linkage for all men born in 1906–1945 asbestos and silica; exposure assessment carcinoma, 5 cases of who were employed in 1970 completed by professional industrial nasopharyngeal cancer, and hygienists 1,831 cases of lung cancer with any exposure to formaldehyde) Significant lung cancer– formaldehyde association may have resulted from residual confounding by smoking, wood dust, asbestos, or crystalline silica Stellman et Cohort = 362,823 men enrolled in the Low-discrimination qualitative exposure High potential for Weak al.
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From page 80... ...
Stroup et al. 1986 Cohort = 2,317 men; outcome: all Moderate-discrimination exposure Exposure was defined aspect of Moderately mortality; buccal cavity and pharyngeal assessment; job structure strongly related job and varied according to type strong Anatomists living in cancer = 1 death, nasal cavity and to exposure; details available for of anatomist the United States sinuses = 0 deaths, lymphohematopoietic duration of association membership and cancer = 18 deaths, leukemia = 10 time period in which anatomists joined deaths, myeloid leukemia = 5 total the association, which were divided into deaths; men who joined American thirds to provide a crude surrogate of Association of Anatomists and lived in cumulative exposure to formaldehyde; United States during 1888–1969 information on research and teaching interests, department affiliations, and membership in other professional associations used to categorize each anatomist as specialist in gross anatomy, microanatomy, both, or neither; on basis of a review of reference materials and on discussions with anatomists who were
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From page 81... ...
2000 Population-based case–control; outcome: High-discrimination quantitative Large, well-conducted study with Strong incidence; 196 newly diagnosed exposure assessment; detailed job, high-discrimination exposure General population nasopharyngeal cancer cases in 1987– industry data from structured interviews; assessment; no assessment of in catchment of 5 US 1993; cases were identified prospectively each job assessed on basis of industrial- peak exposures performed cancer registries (Continued)
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From page 82... ...
and high ≥ 0.50 ppm) ; 13.2% of jobs had ≥10% probability of exposure; coexposure to wood dust was also assessed for each job Walrath and Cohort = 1,132 men; outcome: mortality; Embalmers make up group that has well- Although the cohort was small, Moderately Fraumeni 1983 nasopharyngeal cancer = 0 deaths, defined high exposures to formaldehyde; exposures likely to have been strong sinonasal cancer = 0 deaths, tasks and formaldehyde sources are substantial with good New York state lymphohematopoitic cancer = 25 deaths, defined by regulations, training; double discrimination and qualitative embalmers and leukemia = 12 deaths, myeloid leukemia licensure -- embalmer and funeral distinctions between exposed funeral directors = 6 deaths, nonwhites had 3 deaths from director -- has fewer exposure and not exposed lymphohematopoitic cancer; persons opportunities who died in 1925–1980; 1,132 white, Cohort probably not large male embalmers and funeral directors enough to detect risk of rare licensed in 1902–1980; no duration of cancers, such as sinonasal employment or length of licensure cancer, nasopharyngeal cancer available; persons who held only funeral director's license were not included Walrath and Cohort = 1,007 men; cohort: mortality; Embalmers make up group that has well- Although the cohort was small, Moderately Fraumeni 1984 sinonasal cancer = 0 deaths, defined, high exposures to exposures likely to have been strong lymphohematopoietic cancer = 19 formaldehyde; tasks and formaldehyde substantial with good California state deaths, leukemia = 12 deaths, myeloid sources are defined by regulations, discrimination and qualitative licensed embalmers leukemia = 6 deaths; men who died in training; length of licensure used as distinctions between exposed 1925–1980; white male embalmers surrogate of length of employment and not exposed licensed in 1916–1976; 1,109 deaths; duration of licensure was available but Cohort probably not large not employment enough to detect risk of rare cancers, such as nasal cancer, nasopharyngeal cancers
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, professional industrial-hygienist data analysis, classification of exposures and metrics used, and data on coexposures. See Table 3-1 and discussion of exposure assessment in Appendix C for descriptions and definitions of terms used in this column.
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In practice, therefore, it is common and appropriate to test the associations by using several different summary measures, including cumulative exposure, average exposure, duration of exposure, and peak exposure. It is expected that, on average, choosing the wrong metric will result in an underestimation of an association if one exists (Checkoway et al.
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From page 85... ...
Consistent with those definitions, the presence of negative findings in other studies, especially weak studies, did not necessarily negate positive findings. Nasopharyngeal Cancer The committee reviewed the literature on epidemiologic studies of formaldehyde and nasopharyngeal cancer (see Table 3-3)
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= 7.66 (0.94– n=8 62.34) and test for trend with increasing peak categories p < 0.005 OR for highest cumulative exposure category (≥5.5 ppm–years)
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From page 87... ...
cases identified from Table 2 of the General population in the publication OR derived from the final model that was adjusted for concurrent Philippines effects of education, diesel and dust, smoking, processed meats, n = 26 fresh fish, mosquito coils, and herbal medicines (In some calculations in Table 2 of the publication, n = 27) Abbreviations: ICD, International Classification of Diseases; NCI, National Cancer Institute; NPC, nasopharyngeal cancer; OR, odds ratio; ppm, parts per million.
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From page 88... ...
Its methods included a quantitative exposure assessment with moderate discrimination of who was exposed and the intensity of exposure, and the study was conducted with a well-described expert assessment of formaldehyde exposures classified by self-reported jobs of cases and controls. The estimation of the probability of exposure level or intensity of exposure in each job enabled the investigators to estimate lifetime cumulative exposure of each participant.
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From page 89... ...
The exposure assessment appeared to be a well conducted, semiquantitative assessment with moderate discriminations of exposure and was based on blind expert evaluation of the reported job histories. Several metrics of formaldehyde exposure, particularly in the distant past, were positively associated with nasopharyngeal-cancer incidence.
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From page 90... ...
(2013) was judged to be a strong study because it was well-designed with a high-discrimination, quantitative exposure assessment and it included Poisson regression modeling to control for confounding; however, it contributed little information to the evaluation of formaldehyde exposure and nasopharyngeal cancer in that it was not sufficiently large to detect an effect for rare cancers such as nasopharyngeal cancer.
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From page 91... ...
(2006) conducted a large industrial cohort study of nasopharyngeal cancer incidence in female textile workers in China that included a low-discrimination, qualitative exposure assessment for formaldehyde (years for ever exposed vs never exposed)
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From page 92... ...
It provided evidence of an association between formaldehyde exposure and sinonasal cancer. As mentioned in Chapter 2, a pooled study differs from a meta-analysis in that the data from the studies are combined into a single dataset by using the same or similar case definitions and exposure assessments; this is analogous to what is done in a multisite cohort study.
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From page 93... ...
for rater B Squamous-cell carcinoma with any formaldehyde exposure, low wood-dust exposure: rater A, n = 12; Rater B assigned proportionally more controls to rater B, n = 19 formaldehyde exposure compared with rater A; rating from both raters showed an increase in OR with increasing formaldehyde assignments Luce et al. 1993 Cancer of nasal cavity and paranasal sinuses ICD-9 OR for adenocarcinoma from possible, probable, or definite 160.0, 160.2–160.9; number of cases identified from formaldehyde exposure and no or low wood-dust exposure = General population in France Table 2 of the publication 8.1 (0.9–72.9)
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From page 94... ...
: 5-19 = 1.0 (0.3–2.9) Abbreviations: ICD, International Classification of Diseases; OR, odds ratio; ppm, parts per million; RR, relative risk; SNC, sinonasal cancer.
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From page 95... ...
All of the studies have their own limitations, but taken as a whole they provide corroborating evidence. The moderately strong studies identified by the committee that supported an association between exposure to formaldehyde and sinonasal cancer were Hayes et al.
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From page 96... ...
undertook a population-based case–control study in Washington state of 53 incident cases of sinonasal cancer, including 12 in people thought to have had occupational exposure to formaldehyde. The authors found no evidence of increased risk with maximum exposure, number of years exposed, a cumulative exposure score, or the cumulative exposure score with a 15-year lag period.
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From page 97... ...
Additional details were not provided. Several studies were judged to be moderately strong, but they contributed little information to the evaluation of sinonasal cancer because few subjects who had sinonasal cancer had been exposed to formaldehyde: Walrath and Fraumeni (1983, 1984)
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From page 98... ...
(1998) , in an update of the industrial cohort mortality study of the ACS Cancer Prevention Study-II, found one death from sinonasal cancer in men who had wood-dust exposure and found no evidence of an association with formaldehyde.
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From page 99... ...
. Methodologic Considerations in Exposure Assessment in Studies of Lymphohematopoietic Cancers In the substance profile for formaldehyde, NTP considered the most informative primary studies for the evaluation of lymphohematopoietic cancers to be the study of mortality in the large NCI cohort of formaldehyde-industry workers (Beane Freeman et al.
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From page 100... ...
Some dose metrics are not appropriate for the underlying biology, and when an inappropriate metric is used, a weaker or no dose–response relationship will usually be observed 2 Appendix C provides a general summary of exposure assessments, the rationale for estimating exposures on the basis of physical principles, and a description of methods for measuring airborne formaldehyde exposures.
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From page 101... ...
. The mechanistic process associated with the cumulative exposure and peak exposure metrics appear to be different, and conceptually the metrics should be useful for obtaining insight about the possible mechanism of the effects.
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From page 102... ...
. Those had smaller populations and less discriminating exposure assessments and as a result contributed less to the evidence of an association between formaldehyde and lymphohematopoietic cancers than did the strong studies.
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All All Lymphohematopoi Myeloid Lymphohematopoietic Reference and Study Population etic Cancer Leukemia Leukemia Cancer Leukemia Myeloid Leukemias Andjelkovich et al.
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All All Lymphohematopoi Myeloid Lymphohematopoietic Reference and Study Population etic Cancer Leukemia Leukemia Cancer Leukemia Myeloid Leukemias Meyers et al.
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The RR increased from the group of all lymphohematopoietic cancers to the grouping of all leukemias, and the RR increased further from the grouping of all leukemias to the grouping of myeloid leukemia. Beane Freeman et al.
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From page 106... ...
As a result, this finding is not strong evidence against an association between formaldehyde and myeloid leukemia. As noted earlier in this chapter, the alternative exposure metrics of peak, average, and cumulative exposure are expected to be proportional to the incidence of a disease as related to different biologic mechanisms or pathways.
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From page 107... ...
. The study methods included a high-discrimination, quantitative exposure assessment for current exposures that was performed during the early 1980s, which was an important strength of the study, but it did not cover the full period of exposures.
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From page 108... ...
No other potentially carcinogenic exposures were identified in the plants. As noted above, the exposure assessment had some important limitations.
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From page 109... ...
In the most detailed exposure–response analysis, a nested case– control study, ORs for myeloid leukemia were estimated for four categories of exposure intensity and for a duration 5 years before disease onset. No analysis by duration, cumulative exposure, or other standard continuous exposure metric was presented.
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From page 110... ...
. The study is particularly useful for evaluating the association between formaldehyde exposure and cancer because of the likelihood of high exposures and a high-quality exposure assessment that was conducted by Stewart et al.
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From page 111... ...
All All Reference and Study Lymphohematopoietic Myeloid Lymphohematopoietic Myeloid Population Cancer Leukemia Leukemia Cancer Leukemia Leukemia Hauptmann et al. 2009 168 44 33 Ever embalm: OR = 1.4 Ever embalm: Ever embalm: (lymphohematopoietic (0.8–2.6)
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From page 112... ...
All All Reference and Study Lymphohematopoietic Myeloid Lymphohematopoietic Myeloid Population Cancer Leukemia Leukemia Cancer Leukemia Leukemia (Number of lymphohemtopoietic and leukemia cases identified from Table 3 of the publication; number of cases of myeloid leukemia noted on page 408 of the publication) Walrath and Fraumeni 19 12 6 PMR = 1.2 (0.73–1.90)
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From page 113... ...
(2009) point strongly toward an association between formaldehyde exposure and myeloid leukemia, although measures of associations were stronger in the broad category of all lymphohematopoietic cancers and all leukemias.
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From page 114... ...
Each study had only a handful of leukemia deaths and inadequate exposure assessment that was based on the high likelihood of job exposure to formaldehyde and documentation of years of work. Three of the four studies found a pattern of increasing mortality from leukemia in general and from myeloid leukemia specifically, although few were statistically significant; Walrath and Fraumeni (1983, 1984)
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From page 115... ...
. Each was small with a low-discrimination exposure assessment that did not permit reliable estimation of an association between formaldehyde exposure and any of the types of cancers of interest.
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From page 116... ...
In those whose work histories suggested low or high formaldehyde exposure, the ORs for chronic myeloid leukemia were 1.3 in the low-exposure category (7 cases, 95% CI 0.6–3.1) and 2.9 in the high-exposure category (1 case, 95% CI 0.3–24.5)
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From page 117... ...
Summary of Evidence on Lymphohematopoietic Cancers In summary, the committee concluded that the epidemiologic studies provided evidence of a causal association between formaldehyde and myeloid leukemia in humans. Evidence of an association was derived from two strong industrial cohorts (Beane Freeman et al.
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From page 118... ...
118 FIGURE 3-1 Summary of strrong and moderately strong studies of fo ormaldehyde and lym mphohematopoietic ccancers. Note: Data ppoints connected by a line indicate results from the same stud dy according to the saame exposure metricss but for different tum mor sites.
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From page 119... ...
There is a pattern of positive findings from studies that were judged to be large and strong studies. Low-precision studies, such as those with a small cohort, only a few cases, or limited exposure assessments, may provide some useful data on risk estimates if several studies were performed.
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From page 120... ...
2009) found evidence of increased risk of Hodgkin lymphoma and multiple myeloma in those who had a history of high peak exposures.
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The study was a large industrial case-cohort study (628 incidence lung-cancer cases) of Chinese female textile workers and it had detailed exposure assessment.
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CANCER STUDIES IN EXPERIMENTAL ANIMALS This section reviews the evidence of carcinogenicity in experimental animal studies and applies the NTP criteria to produce the committee's independent evaluation. In reviewing the evidence, the committee looked at primary literature and considered analyses in other reviews, including those by the International Agency for Research on Cancer (IARC 1982, 1995, 2006a)
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From page 123... ...
and squamous-cell metaplasia al. 1988 Only nasal cavity examined Wistar rats Relatively small initial group Forestomach hyperkeratosis, basal Tobe et al.
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From page 124... ...
. The authors reported increased rates of nasal epithelial cell-proliferation with squamous-cell metaplasia of the transitional and respiratory epithelia of the nasal passages and squamous-cell metaplasia of the respiratory epithelia of the trachea and large airways of the bronchial tree.
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From page 125... ...
TABLE 3-9 Nasal Squamous-Cell Carcinoma in Long-Term Inhalation Studies of Formaldehyde1 Concentrations in Air (Incidences) Species and Study Duration Strain (week)
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126 TABLE 3-9 Continued Concentrations in Air (Incidences) Species and Study Duration Strain (week)
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From page 127... ...
However, diffuse multifocal bone marrow hyperplasia in formaldehyde-exposed animals was increased in both treated males (six of 114 controls vs 26 of 111 treated, p = 0.0001) and females (seven of 113 controls vs 28 of 115 treated, p = 0.0001)
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From page 128... ...
Committee Evaluation in the Context of the Report on Carcinogens Listing Criteria Applying the NTP criteria to the bioassay data for formaldehyde, the committee draws the following conclusions about exposure to formaldehyde in experimental animals:
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From page 129... ...
. The committee concludes that there is sufficient evidence that formaldehyde is carcinogenic in experimental animals.
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2011) and in animal models (Wu et al.
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Inhalation Dosimetry Because inhalation is the most likely route of exposure to formaldehyde, an understanding of the fate of inhaled formaldehyde is critical for evaluation of its toxicity. As would be expected for a water-soluble highly reactive gas (Kimbell 2006)
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From page 132... ...
. The models suggest that inhaled formaldehyde is not deposited uniformly throughout the nose, but local areas, "hot spots", receive a higher delivery of the dose than other areas.
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From page 133... ...
Formaldehyde is clearly cytotoxic to the nasal epithelium, and the nasal epithelial basal cells are probably the target for nasal tumorigenesis; this indicates that reactive formaldehyde penetrates to this depth in the nose. Given the shallow slope of the concentration–tissue depth profile, it is likely that toxicologically significant concentrations of formaldehyde penetrate somewhat deeper to the superficial capillary layer of the nose, inasmuch as these capillaries are adjacent to the basement membrane and basal
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From page 134... ...
134 Review R of the Fo ormaldehyde Asssessment in the N NTP 12th Repoort on Carcinogeens FIGUR RE 3-3 Schematiic representation n of the structuree of the nasal muucosa of the resppiratory eppithelium and follicle-associate fo d epithelium. F For both epitheliia, a concentratiion gradientt for exogenous formaldehyde during d inhalationn exposure will exist with conceentrations at the superficial layer (closestt to the airstream m)
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From page 135... ...
Indepen ndent Assessmeent of Formaldeehyde 1135 FIGUR RE 3-4 Model-baased estimates of o exogenous forrmaldehyde conncentration in naasal tissues during d inhalation n exposure to 6 ppm p formaldehyyde. Tissue conccentrations increaase quickly from 0.1 to 0.5 minutes after th he onset of expoosure as a quasii-steady state is establisheed.
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From page 136... ...
One study reported increases in blood albumin–formaldehyde adducts in workers exposed to formaldehyde (Pala et al.
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From page 137... ...
There is evidence that exogenously administered formaldehyde is responsible for noncancer and cancer effects at the portal of entry, such as nasal mucosa or other parts of the upper aerodigestive tract, depending on the mode of administration and breathing patterns. It has been more controversial whether formaldehyde itself or products of its biotransformation may reach tissues that do not come into direct contact with inhaled or ingested formaldehyde in experimental animals or humans, and a detailed discussion of the available evidence is provided under the section "Toxicokinetics" above.
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From page 138... ...
The committee focused its attention on the mechanistic evidence that is related to genotoxicity and mutagenicity, hematologic effects, and data from toxicogenomic studies, which reflects broad biologic responses and is thus informative as both the overall effect and specific pathways that may be perturbed by exposure to formaldehyde. The RoC does not present quantitative assessments of risks of cancer associated with the substances listed.
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A series of key events causally related to the toxic effect are then identified using an ap proach based on the Bradford Hill criteria and compared qualitatively and quantitatively between experimental animals and humans.
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. In each table, the committee separated studies by type of the model system, including a clear division between the portal-of-entry and systemic effects in in vivo studies.
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# M1G adduct has been postulated to be the result of secondary DNA damage caused by formaldehyde-associated oxidative stress. Abbreviations: DNA, deoxyribonucleic acid; DDX, DNA–DNA cross-links; DPX, DNA–protein cross-links; SCE, sister-chromatid exchanges; MN, muconuclei; CA, chromosomal aberrations.
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From page 142... ...
The latter two are most relevant to the determination of the cancer-hazard classification according to the RoC listing criteria, which call for conclusions to be based on the information "derived from the study of tissues or cells from humans exposed to the substance in question" (NTP 2011, p.
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From page 143... ...
For example, DNA–protein cross-links were formed in a concentration–response manner in human lymphoblastoid cell lines (Ren et al.
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From page 144... ...
are comparable with or an order of magnitude higher than those documented in human occupational exposures. The shape of the concentration–response curve of several biomarkers of genotoxicity in the portal-of-entry tissues in rodents is nearly identical with that for tumorigenesis in the noses of rodents (Swenberg et al.
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From page 145... ...
Studies of nonhuman primates found no evidence of the increased formation of DNA adducts in bone marrow after exogenous administration of 13C-labeled formaldehyde (Moeller et al.
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From page 146... ...
The evidence is consistent and strong, albeit it is difficult to establish unequivocal specificity of the effects following exposure to formaldehyde in the human studies. Whereas the committee recognizes some inconsistencies among data in experimental animals and humans and among genotoxicity biomarkers, this variability does not undermine the committee's conclusion.
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From page 147... ...
The focus of this section is on evaluation of recently available evidence related to the hematologic effects of formaldehyde in human and animal exposure studies and evidence that is available from in vitro studies. Hematologic Effects in Humans Exposed to Formaldehyde Hematologic effects of formaldehyde include effects on cells of the hematopoietic system that are circulating in the peripheral blood, are present in hematologic tissues (such as bone marrow, lymph nodes, and spleen)
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From page 148... ...
ppm vs <0.03 ppm Workers (43 Factory workers exposed Peripheral blood measures Reanalysis of Zhang et al.
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From page 149... ...
2010 (37 formaldehyde- exposed women in four for apoptosis, proliferation, 77% higher in formaldehyde-only exposed workers exposed, 37 controls) pathology departments HPRT function, UV-induced compared with controls.
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From page 150... ...
At 3.0 mg/m3 of formaldehyde, NFkB exposure in increased by 34%, and inflammatory cytokines were animals increased -- TNFα by 42% and IL-1b by 98%. Female C57BL/6 Inhaled formaldehyde at BM, lymph node, spleen, Formaldehyde-exposed mice showed 30% increase in Kim et al.
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From page 151... ...
. Female Wistar rats Inhaled formaldehyde, Blood and bone marrow Sham-control rats were part of a larger study of female Lino-dos-Santos nebulized at 0.32%, 90 samples measured for cell sex hormone effects on formaldehyde-induced airway Franco et al.
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Abbreviations: AML, acute myeloid leukemia; B, bursa-derived cells; BAL, bronchoalveolar lavage; BM, bone marrow; BrdU, bromodeoxyuridine; CA, chromosomal aberrations; CD, cluster of differentiation; CFU-GM, colony-forming unit-granulocyte-macrophage; CYP1A1, cytochrome P450, family 1, subfamily A, polypeptide 1; DNA, deoxyribonucleic acid; FANCD2, fanconi anemia group D2 protein; GSTT1, glutathione s-transferase theta 1; HPRT, hypoxanthine-guanine phosphoribosyltransferase; GSH, glutathione; IFNg, interferon gamma; IgG, immunoglobulin G; IgM, immunoglobulin M; IL-1b, interleukin-1 beta; LPS, lipopolysaccharide; Ly49 - killer cell lectin-like receptor subfamily A; mg/m3, milligram per cubic meter; mg/mL, milligrams per milliliter; MN, micronucleus test; MSC, mesenchymal stem cell; MTT, methylthiazol tetrazolium; NFkB, nuclear factor kappa-light-chain-enhancer of activated B cells; NK, natural killer cells; PBMC, peripheral blood mononucleated cell; PHA, phytohemagglutinin; ppm, parts per million; ROS, reactive oxygen species; SCE, sister-chromatid exchange; T, thymus cells; TCR, T-cell receptors; TNFa, tumor necrosis factor alpha; TWA, time-weighted average; UV, ultraviolet; WBC, white blood cell count. Source: Committee generated.
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2010 Neutrophils ↓ spontaneous respiratory burst activity Lyapina et al. 2004 ↑ susceptibility to infection 153 (Continued)
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2013 Erythrocytes ↓ expansion of human erythroid progenitor cells in vitro Ji et al. 2013 MSCs ↓ viability of bone marrow stromal cells She et al.
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In light of the numerous studies that have reported significant differences in multiple measures, there is a strong association between inhaled formaldehyde exposure in humans and hematologic effects. Although confounding exposures may complicate the interpretation of some studies, most of the studies documented efforts to identify possible confounding factors.
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. All six studies reported deleterious effects of formaldehyde exposure on T cells, B cells, NK cells, or bone marrow stromal cells; this suggests that formaldehyde may have hematologic effects if it comes into direct contact with these cell types.
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Taken as a whole, the body of evidence from studies of exposed humans and animals indicates broad and strong associations between exposure to inhaled formaldehyde and hematologic effects. Toxicogenomics Toxicogenomics is the study of gene-expression changes elicited by a toxicant.
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Differentially expressed genes identified in the three exposure groups showed little overlap. No significant specific pathways involving differentially expressed genes were apparent.
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protease mixture Rats: Formaldehyde Nasal surface 1.5-fold; No differentially expressed genes were Andersen et male F344/CrlBR vapor or instillation epithelial cells Benjamini- detected after exposure to formaldehyde al. 2008 (lateral meatus and Hochberg; FDR vapor at 0.7 ppm.
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Exposure to 100 μM formaldehyde for 4 hours caused 1,367 differentially expressed genes, whereas
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Abbreviation: FDR, false discovery rate. a Criteria for defining differentially expressed genes.
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The committee found multiple studies that reported transcriptional responses in nasal cavity epithelial cells from experimental animals exposed to formaldehyde vapor at doses of 2 ppm or greater. The transcriptomal responses were indicative of cell apoptosis, DNA damage, and proliferation, which are relevant to carcinogenesis.
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Nasopharyngeal and Sinonasal Cancers The committee found clear and convincing epidemiologic evidence of an association between formaldehyde exposure and nasopharyngeal cancer and sinonasal cancer in humans. On the basis of evidence of an association between nasopharyngeal cancer and exposure to formaldehyde in two strong studies -- a large case–control study (Vaughan et al.
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Myeloid Leukemia The committee found clear and convincing epidemiologic evidence of an association between formaldehyde exposure and myeloid leukemia. There may also be an increase of other lymphohematopoietic cancers, although the evidence is less robust.
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The committee concludes that these findings provide plausible mechanistic pathways supporting a relationship between formaldehyde exposure and cancer, even though the potential mechanisms of how formaldehyde may cause such systemic effects are not fully understood. It would be desirable to have a more complete understanding about how formaldehyde exposure may cause systemic effects, but the lack of known mechanisms should not detract from the findings of an association between formaldehyde exposure and myeloid leukemia in epidemiology studies.
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Also, and importantly, the RoC listing criteria require an association in only one type of cancer to make the determination. On the basis of the information summarized directly above for nasopharyngeal cancer, sinonasal cancer, and for myeloid leukemia, the committee makes its independent determinations as follows: There is sufficient evidence of carcinogenicity from studies of humans based on consistent epidemiologic findings on nasopharyngeal cancer, sinonasal cancer, and myeloid leukemia for which chance, bias, and confounding factors could be ruled out with reasonable confidence.
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2008. Ge nomic signatures and dose-dependent transitions in nasal epithelial responses to inhaled formaldehyde in the rat.
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2014. Upper airway cancer, myeloid leukemia, and other cancers in a cohort of British chemical workers exposed to for maldehyde.
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1993. A cohort study of workers exposed to formaldehyde in the British chemical industry: An update.
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1996. Occupational exposure to formaldehyde and risk of cancer [in Danish]
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2001. Occupational exposure to wood, formaldehyde, and solvents and risk of nasopha ryngeal carcinoma.
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2006. Occupational risk factors for nasopharyngeal cancer among female textile workers in Shanghai, Chi na.
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2002. Sinonasal cancer and occupational exposures: A pooled analysis of 12 case-control studies.
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2010b. Exposure of human nasal epithelial cells to formaldehyde does not lead to DNA damage in lymphocytes after co-cultivation.
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1987. Nasopharyngeal cancer, sinonasal cancer, and occupations related to formalde hyde: A case-control study.
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2012. Occupational exposure to wood dust and formaldehyde and risk of nasal, nasopharyngeal, and lung cancer among Finnish men.
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2000. Occupational exposure to formaldehyde and wood dust and naso pharyngeal carcinoma.
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2013. Inhaled formaldehyde induces DNA-protein crosslinks and oxidative stress in bone marrow and other distant organs of exposed mice.
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Key Terms
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