Occupational Exposure to Formaldehyde and Leukemia

Background: Leukemia

  1. Leukemias represent 3% of all malignant neoplasms. Ionizing radiation, benzene, and cytotoxic drugs are known causes of acute leukemia. [Rosenstock, p. 746-7]
  2. The American Cancer Society estimates that in 2013, there will be 48,610 new cases of leukemia diagnosed. The main types of leukemia are: Acute myeloid leukemia (AML): 30%; Acute lymphoid leukemia (ALL): 12.5%; Chronic lymphoid leukemia (CLL); 32%; Chronic myeloid leukemia (CML): 12%; Chronic myelomonocytic leukemia (CMML): 2%; Other or "not otherwise classified": 11.5%;
  3. There is strong evidence for associations between the following and occupational leukemia: boot and shoe manufacture and repair, benzene, ionizing radiation, and ethylene oxide. The evidence for formaldehyde is suggestive.  [Siemiatycki, p. 334]
  4. "There is sufficient evidence in humans for a causal association of formaldehyde with leukemia." [IARC 2012: Formaldehyde]
  5. "The four major categories of leukemia considered in this chapter are acute myeloid (including acute monocytic), chronic myeloid, acute lymphocytic, and chronic lymphocytic leukemia.  . . . . In the United States, other and not otherwise specified leukemia currently comprises 7.8% of the total, more than half of which (4.7%) are other acute leukemias." [Schottenfeld, p. 841]
  6. "The disorders of myeloid origin include acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and myeloproliferative disorders (MPD) (the latter including chronic myeloid leukemia (CML). . . . MDS, CML, and the other MPD may all transform to AML." [Schottenfeld, p. 842]
  7. "Because MDS and AML are often evaluated together or sometimes considered as a single entity, and there are few epidemiological studies focusing solely on MDS, the analytical studies for both conditions are summarized together in the following section." [Schottenfeld, p. 845]
  8. "Leukemia outcomes reported in epidemiological studies of radiation-exposed populations often include all leukemias combined for mortality because subtypes are frequently not provided on death certificates. . . . The epidemiological findings for all leukemias other than chronic lymphocytic leukemia (hereafter designated non-CLL) are described in this section because AML, CML, and ALL are often considered as a combined entity and radiation-related risks are not ascertained or quantified for the individual leukemia entities." [Schottenfeld, p. 846]
  9. "Chronic lymphocytic leukemia (CLL) is classified with the lymphomas as one of the peripheral lymphoproliferative diseases in the WHO Classification. We include CLL in this chapter on the leukemias because until recently CLL was frequently designated as one of the four major categories of the leukemias." [Schottenfeld, p. 853]
  10. "Lymphoid leukemias comprise 47.5% of total leukemias in the United States, including 11.3% ALL, 32.2% CLL, and 4.0% other lymphoid leukemia. . . The age-specific incidence pattern for ALL is quite distinctive, with a peak at ages 2-4." [Schottenfeld, p. 854]
  11. According to Harrison, p. 417, the relative frequency of lymphoid malignancies are: Non-Hodgkin's lymphoma: 62.4%; Plasma cell disorders: 16%; CLL: 9%; Hodgkin's disease 8.2%; ALL: 3.8%;
  12. "The cause of CLL is unknown." [Cecil, p. 1214]
  13. "The exact cause of most cases of chronic lymphocytic leukemia (CLL) is not known. But scientists have learned a great deal about the differences between normal lymphocytes and CLL cells in recent years." [American Cancer Society]
  14. "AML is a clonal malignancy of myeloid bone marrow precursors in which poorly differentiated cells accumulate in the bone marrow and circulation. . . . In the United States about 13,780 cases have occurred in 2012. AML accounts for about 80% of acute leukemias in adults. Etiology is unknown for the vast majority. Three environmental exposures increase the risk: chronic benzene exposure, radiation exposure, and prior treatment with alkylating agents . . . Chronic myeloid leukemia (CML), myelodysplasia, and myeloproliferative syndromes may all evolve into AML." [Harrison, p. 403]
  15. "Further studies of benzene-exposed groups are needed to ascertain risks of leukemia types other than AML and aplastic anemia, and to determine whether other hematopoietic or lymphoproliferative malignancies occur excessively." [Schottenfeld, p. 859]

Background: Formaldehyde

  1. "Formaldehyde is found as a natural product in most living systems and in the environment. It occurs naturally in fruits and some foods, and it is formed endogenously in mammals, including humans, as a consequence of oxidation metabolism." [IARC 2012: Formaldehyde, p. 402]
  2. "Formaldehyde is mutagenic and, when inhaled at high concentrations, carcinogenic in rats." [Coggon 2003, p. 1608]
  3. "Experimental data indicate that in rats, the carcinogenic activity of formaldehyde is associated with cytotoxic/proliferative mechanisms. Therefore protecting from these effects associated with formaldehyde exposure should be sufficient to protect from its potential carcinogenic effects, if any in humans." [Duhayon 2008, p. 695]
  4. "Nevertheless, interpretation of the biologically based animal cancer risk assessment data indicates that the oncogenic potential of formaldehyde is a threshold phenomenon and that prevention of upper respiratory tract irritation and the associated regenerative hyperplasia should eliminate, for all practical purposes, any excess cancer risk posed by occupational formaldehyde exposure alone." [ACGIH, Formaldehyde, 2001]
  5. History of ACGIH TLVs: 5 ppm (1948-1962); 5 ppm Ceiling (1963-1971); 2 ppm Ceiling (1972-1984); 1 ppm (1985-1991); 0.3 ppm Ceiling (1992-present); [ACGIH, Formaldehyde, 2001]
  6. The OSHA Permissible Exposure Level for formaldehyde is 2 ppm as a short term exposure limit (STEL) and 0.75 ppm as an eight-hour TWA. The ACGIH Ceiling is 0.3 ppm. Formaldehyde is designated as A2 (Suspected Human Carcinogen) by ACGIH and 4 by the German MAK Commission. A 4 designation is defined as "Substances with carcinogenic potential for which genotoxicity plays no or at most a minor role. No significant contribution to human cancer risk is expected, provided the MAK value is observed."  [Guide to Occupational Exposure Values]
  7. "We examined the ability of formaldehyde to disrupt hematopoiesis in a study of 94 workers in China (43 exposed to formaldehyde and 51 frequency-matched controls) by measuring complete blood counts and peripheral stem/progenitor cell colony formation. Further, myeloid progenitor cells, the target for leukemogenesis, were cultured from the workers to quantify the level of leukemia-specific chromosome changes, including monosomy 7 and trisomy 8, in metaphase spreads of these cells. Among exposed workers, peripheral blood cell counts were significantly lowered in a manner consistent with toxic effects on the bone marrow and leukemia-specific chromosome changes were significantly elevated in myeloid blood progenitor cells. These findings suggest that formaldehyde exposure can have an adverse effect on the hematopoietic system and that leukemia induction by formaldehyde is biologically plausible, which heightens concerns about its leukemogenic potential from occupational and environmental exposures." [Zhang 2010, p. 80]
  8. "All exposed workers had to meet two inclusion criteria: (a) they had to have had formaldehyde exposure levels of about 1 to 2 ppm on most days during the initial screening and (b) they held the same job for at least the previous 3 mo in the same factory." [Zhang 2010, p. 82] 
  9. "With an average exposure of 1.28 ppm as an 8-hour time-weighted average, which is somewhat higher than the U.S. permissible exposure limit of 0.75 ppm, the subjects in our study were highly exposed and may explain why we were able to see hematotoxic effects in a relatively small population." [Zhang 2010, p. 86]

Background: Epidemiology Studies Cited by IARC 2012 Monograph: Formaldehyde

  1. "A recently published nested case–control study conducted among professionals in the funeral industry examined lifetime work practices and exposure in the funeral industry to develop metrics of exposure among this group, which included duration of jobs held while embalming, number of embalmings, average intensity of embalming and peak exposure (Hauptmann et al., 2009). Details of work practices were obtained by interviews with next of kin and co-workers. Positive associations were seen – at many levels of exposure and for multiple exposure metrics – for deaths from lymphohaematopoietic malignancies of nonlymphoid origin (n = 48). For myeloid leukaemia (n = 34) the OR was 13.6 (95%CI: 1.6–119.7; Ptrend = 0.020) for the longest duration of work in jobs with embalming." [p. 406]
  2. "The findings for leukaemia in studies of professional workers appeared to be contradicted by the lack of such findings among industrial workers. However, some evidence for an excess of deaths from leukaemia has been reported in the recent updates of two of the three major cohort studies of industrial workers." [p. 406]
  3. "The updated study of British industrial workers found no excess mortality for leukaemia among all workers exposed to formaldehyde (SMR = 0.91; 95%CI: 0.62–1.29) or among those with the highest exposure (SMR = 0.71; 95%CI: 0.31–1.39) (Coggon et al., 2003). The lack of positive findings in this study is difficult to reconcile with the findings from the studies of garment workers and industrial workers in the USA, and with the results of studies on professionals exposed to formaldehyde. This British study is a relatively large, high-quality study with sufficiently long follow-up to have had a reasonable chance to detect an excess of deaths from leukaemia." [p. 407]
  4. "The Working Group was not in full agreement on the evaluation of formaldehyde causing leukaemias in humans, with a small majority viewing the evidence as sufficient of carcinogenicity and the minority viewing the evidence as limited." [p. 430]

Background: Coggon 2003

  1. "The cohort was composed of 14 014 men who had been employed at six British chemical factories at at time when formaldehyde was produced or used and for which personnel records were believed to be complete. . . . No measurements of formaldehyde had been taken before 1970, but from later measurements and from workers' recall of irritant symptoms, it is estimated that background exposure corresponded to time-weighted average concentrations of less than 0.1 ppm; low exposure to 0.1-0.5 ppm; moderate exposure to 0.6-2.0 ppm; and high exposure to greater than 2.0 ppm." [p. 1608-9]
  2. For all factories combined in the total cohort from 1941-2000, deaths from leukemia were 31 observed and 34.1 expected. For men with high exposure, 1941-2000, deaths were 8 observed and 11.3 expected. [p. 1611, Table 5]

Background: Beane Freeman 2009

  1. "For peak exposure, the highest formaldehyde-related risks for myeloid leukemia occurred before 1980, but trend tests attained statistical significance in 1990 only. After the mid-1990s, the formaldehyde-related risk of myeloid leukemia declined." [p. 751]
  2. "The cohort consists of 25 619 workers employed in one of 10 industrial plants in the United States before January 1, 1966. The 10 plants were manufacturers of formaldehyde, formaldehyde resins, or molding compounds or were major users of formaldehyde resins or molding compounds, including molded plastic products, decorative laminates, photographic film, and plywood. The original study included deaths through 1979; an extension of this study added deaths from the beginning of 1980 through December 31, 1994." [p. 752]
  3. "Exposure to formaldehyde was estimated for each job from individual work histories abstracted in 1980." [p. 753]
  4. "No statistically significant associations were observed with average intensity (Table 3) or cumulative exposure to formaldehyde (Table 4). For the highest peak exposure, there was a non-statistically significant elevated relative risk for myeloid leukemia (RR = 1.78; 95% CI = 0.87 to 3.64, P trend = .13). When including all person-years (both unexposed and exposed), the P trend was .07. For the highest average intensity, there was a statistically nonsignificant increase for myeloid leukemia (RR = 1.61; 95% CI = 0.76 to 3.39; P trend = .43)." [p. 754]
  5. "For peak exposure, the cumulative risk estimates, calculated by extending follow-up by yearly increments for the highest exposure category, remained statistically significant throughout but decreased when extending the follow-up beyond 1980. Relative risks with average intensity were at or near their maxima when follow-up ended in the 1980s and declined with accrual of additional person-years and events." [p. 756]
  6. "In the current follow-up, the overall risk of myeloid leukemia has declined from our previous report, but remains somewhat elevated. Although that time trend may suggest that the previous excess risk estimates were due to chance, the pattern is consistent with a possible causal association, with the largest risks occurring closer in time to relevant exposure. The wavelike pattern of the relative risks over time resembles that seen for known leukemogenic agents." [p. 760]

Background: Hauptmann 2009

  1. "For lymphohematopoietic malignancies, risks were assessed for malignancies of lymphoid (n = 99; ICD-8 200 – 204) or nonlymphoid (n = 48; ICD-8 205, 206, 208, or 209) origin and, as a separate rubric, myeloid leukemia (n = 34; ICD-8 205)." [p. 1697]
  2. "Study design: In a case-control study in a cohort of deceased funeral industry workers, those who died from lymphohematopoietic malignancies and brain tumors were compared with control subjects. Lifetime work practices and exposures to formaldehyde were obtained by interviews with next of kin and coworkers." [p. 1697]
  3. "Contribution: The number of years of embalming practice and related formaldehyde exposures in the funeral industry was associated with statistically significantly increased mortality from myeloid leukemia. No associations were observed with other lymphohematopoietic malignancies." [p.1697]
  4. "Most subjects began to work in a funeral home before 1950 when they were aged 28 years or younger, and many had worked in funeral homes beyond age 65 years." [p. 1699]
  5. "Increasing years of embalming practice, compared with having never embalmed, were associated with statistically significantly increasing risks for lymphohematopoietic malignancies of nonlymphoid origin ( P for trend = .046; eg, among those who embalmed for more than 20 years, OR = 3.5, 95% CI = 1.1 to 10.9, P = .034, data not shown)." [p. 1699]
  6. "Among the 34 deaths from myeloid leukemia, 20 were acute, 12 were chronic, and four (including the one death in the nonexposed group) were unspecified." [p. 1701]
  7. "When we compared this study in the funeral industry with the National Cancer Institute cohort study of formaldehyde industries, we found that funeral home workers who embalm tended to have longer duration of formaldehyde exposure and  higher cumulative levels of formaldehyde exposure but lower 8-hour time-weighted average intensity. Peak exposure levels of greater than 4 ppm, the lower bound of the highest exposure category in the analysis of the industrial cohort study, appear to be more common among embalmers (ie, 77% of control subjects) than among industrial workers (ie, 25% of workers). Our study assessed work in the funeral industry approximately through the early 1980s and so the work patterns and estimated exposure levels of deceased control subjects may not be entirely representative of current practice in the funeral industry. However, the average estimated formaldehyde intensity while embalming among control subjects (1.7 ppm, SD = 0.7 ppm; Table 2) was generally consistent with levels that were reported previously in limited surveys of funeral homes, which tend to show average exposure levels in the range of 1 ppm." [p. 1706-7]

Background: Pinkerton 2004

  1. "A non-significant increase in mortality from myeloid leukaemia (15 deaths, SMR 1.44, 95% CI 0.80 to 2.37) was observed. Mortality from myeloid leukaemia was greatest among workers first exposed in the earliest years when exposures were presumably higher, among workers with 10 or more years of exposure, and among workers with 20 or more years since first exposure." [p. 193]
  2. "These garment facilities produced shirts from fabrics which were treated with formaldehyde resins to impart crease resistance and other desirable properties. The fabrics emitted formaldehyde gas resulting in potential occupational exposures. Employees who had worked at least three months after formaldehyde was first introduced into the production process were included in the cohort. Formaldehyde was first introduced in 1959 at plants 1 and 2, and in 1955 at plant 3. Clerical and administrative employees were not included." [p. 193]
  3. "Data on personal exposure levels of formaldehyde for 549 randomly selected employees in five different departments (cutting, collar, parts, assembly, and packaging) are available for 1981 (plant 1) and 1984 (plants 2 and 3). Briefly, exposure to formaldehyde was similar across departments and plants; the geometric mean eight hour time weighted average (TWA) exposure to formaldehyde across all departments and plants ranged from 0.09 to 0.20 ppm. The overall geometric mean concentration of formaldehyde was 0.15 ppm (geometric standard deviation 1.90). Area monitoring showed that the formaldehyde levels were essentially constant without substantial peaks or intermittent exposures. Additional information on the exposure levels found is available elsewhere. Information on historical exposure levels to formaldehyde was not available for these plants. However, formaldehyde exposures were believed to have been substantially higher in earlier years because the resin systems used in treating permanent press fabrics had been improved to reduce the amount of formaldehyde in the fabrics." [p. 194]
  4. "The duration of exposure of the cohort is relatively short with a median of 3.3 years." [p. 195]
  5. "In contrast, mortality from leukaemia was not increased among 26 561 workers employed at 10 US formaldehyde producing or using plants, or among 14 037 men employed at six British formaldehyde producing or using plants. Both of these studies included workers who were exposed to much higher levels of formaldehyde (>2 ppm) than those measured at the plants in this study in the 1980s. Workers in our study were probably exposed to higher concentrations of formaldehyde in earlier years than in the 1980s, but the level of exposure is unknown." [p. 199]

What extent/how many years of exposure to formaldehyde are necessary to develop leukemia? 

  1. Embalmers in the funeral industry in the 1950s through the early 1980s, who were commonly exposed to peak levels of formaldehyde greater than 4 ppm, had increased incidence of leukemia compared to controls. Myeloid leukemia was associated with high-level exposures of more than 34 years of employment in embalming, more than 3068 embalmings, and more than 9253 ppm-hours of cumulative formaldehyde exposure. [Hauptmann et al.]
  2. In a study of 14 037 men working at six British formaldehyde producing of using plants and described by IARC as "relatively large, high-quality study with sufficiently long follow-up to have had a reasonable chance to detect an excess of deaths from leukaemia," mortality from leukemia was not increased. For all factories combined in the total cohort from 1941-2000, deaths from leukemia were 31 observed and 34.1 expected. For men with high exposure, 1941-2000, deaths were 8 observed and 11.3 expected. [Coggon et al., p. 1611, Table 5]

Is there a latency period between exposure and disease development?

  1. In atomic bomb survivors, the incidence of acute leukemias peaked at 2 to 5 years and declined after 10 years. After chemotherapy, the incidence peaks at 5 to 8 years. [Rosenstock, p. 746-7]
  2. Significant benzene exposure increases the risk of leukemia during the 10 years following exposure. Risk is not related to exposures that occurred greater than 20 years prior to the onset of disease. [Leukemia after exposure to benzene: temporal trends and implications for standards.]
  3. "The overall associations of formaldehyde exposure with leukemia and myeloid leukemia in the NCI cohort have diminished with an additional 10 years of follow-up since our previous analysis. For peak exposure and myeloid leukemia, the cumulative risk estimates were highest before 1980 but only achieved statistical significance in the early 1990s, after which they slowly declined. This pattern could reflect the increased precision of the relative risk estimates with accrual of additional person-years and myeloid leukemia cases or could reflect a relatively short induction-incubation time for myeloid leukemia because analyses by time since first exposure and first high peak both indicate highest risks within the first 25 years." [Beane Freeman et al., p. 756-7]

What type of jobs or labor categories would be most involved?

  1. "The highest continuous exposures (2-5 ppm; 2.5-6.1 mg/m3) were measure in the past during varnishing of furniture and wooden floors, in the finishing of textiles, in the garment industry, in the treatment of fur, and in certain jobs within manufactured board mills and foundries. Short-term exposures to high levels (3 ppm and higher; >3.7 mg/m3) have been reported for embalmers, pathologists, and paper workers. Lower concentrations have usually been encountered during the manufacture of man-made vitreous fibers, abrasives, and rubber, and in formaldehyde-production industries." [IARC 2012: Formaldehyde, p. 403-4]
  2. "Stewart et al. traced mean historic and current formaldehyde concentrations for 30,000 employees of manufacturers of formaldehyde, formaldehyde resins, or molding compounds or for major consumers of those agents (molded plastic products, decorative laminates, photographic film, and plywood paneling manufacture). The collected data showed that from 1946 to 1955, formaldehyde concentrations averaged 1.00 to 1.15 ppm; from 1956 to 1967, 0.90 to 0.95 ppm; from 1968 to 1971, 0.65 to 0.70 ppm; from 1972 to 1979, 0.45 to 0.50 ppm; and from 1980 to 1981, 0.35 to 0.38 ppm. During normal installation and varnishing work, carpet and parquet tile fitters were exposed to mean ambient formaldehyde levels of 4.3 ppm (2.55 to 6.06 ppm). The mean ambient formaldehyde concentration in 77 Houston, Texas, fabric stores was 0.14 + 0.07 ppm, with 24-hour TWA values of up to 0.28 ppm." [ACGIH, Formaldehyde, 2001]

References

  1. 2012. IARC Monograph: Formaldehyde
  2. 2010. Zhang L. Occupational exposure to formaldehyde, hematotoxicity, and leukemia-specific chromosome changes in cultured myeloid progenitor cells.
  3. 2009. Beane Freeman LE. Mortality from lymphohematopoietic malignancies among workers in formaldehyde industries: the National Cancer Institute Cohort.
  4. 2009. Hauptmann M. Mortality from lymphohematopoietic malignancies and brain cancer among embalmers exposed to formaldehyde.
  5. 2008. Duhayon S. Carcinogenic potential of formaldehyde in occupational settings: a critical assessment and possible impact on occupational exposure levels.
  6. 2004. Pinkerton LE. Mortality among a cohort of garment workers exposed to formaldehyde: an update.
  7. 2003. Coggon D. Extended follow-up of a cohort of british chemical workers exposed to formaldehyde.
  8. 2000. Finkelstein MM. Leukemia after exposure to benzene: temporal trends and implications for standards.
  9. ACGIH - Documentation of the TLVs and BEIs, 7th Ed. Cincinnati: ACGIH Worldwide, 2008.
  10. Cecil - Goldman L, Schafer AI (eds). Cecil Medicine, 24th Ed. Philadelphia: Elsevier, 2012.
  11. Guide to Occupational Exposure Values - Compiled by ACGIH. Cincinnati: ACGIH Worldwide, 2013.
  12. Harrison - Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J (eds). Harrison's Manual of Medicine, 18th Ed. New York: McGraw Hill, 2013.
  13. Rosenstock L, Cullen MR, Brodkin CA, Redlich CA (eds). Textbook of Clinical Occupational and Environmental Medicine, 2nd Ed. Philadelphia: Elsevier Saunders, 2004.
  14. Siemiatycki J, Richardson L, Boffetta P. Occupation. In: Schottenfeld D, Fraumeni JF. Cancer Epidemiology and Prevention, 3rd Ed. New York: Oxford University Press, 2006.
  15. Schottenfeld D, Fraumeni JF (eds). Cancer Epidemiology and Prevention, 3rd Ed. New York: Oxford University Press, 2006.

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