Formaldehyde Carcinogenicity as Safety Concern

In 1989, American Medical Association summarized literature data through 1985 on formaldehyde occupational exposure. By mentioning that regulatory agencies as OSHA, regard formaldehyde as a possible human carcinogen, AMA noticed that “this is a controversial opinion in the view of many industry and academic scientists.”  During the 80th, there was a politically charged dispute between EPA, OSHA, CAP, Formaldehyde Institute, DuPont and labor unions on evaluation of occupational exposure risk that was based at that time on formaldehyde assessment as “probable carcinogen.”1

The main organization that influences the assessment of reagents as carcinogenic is the World Health Organization’s (WHO) International Agency for Research on Cancer (IARC) based inLyon,France. IARC summarizes literature data predominately epidemiological research, as well as some experimental studies.

According to IARC Press Release No 153, 15 June 2004 formaldehyde is placed in Group I – known carcinogens- along with such substances as asbestos and benzene.2

It is reasonable to quote excerpts from Summary of Data Reported and Evaluation (in red italic, with main points in bold) of the IARC Monographs Programme on Formaldehyde 2006.3 The complete text is 496 pages. Comments will accompany main conclusions, as well as some relevant anatomical data.

5.2 Human data

Nasopharyngeal cancer

“Overall, the Working Group concluded that the results of the study of industrial workers in the USA, supported by the largely positive findings from other studies, provided sufficient epidemiological evidence that formaldehyde causes nasopharyngeal cancer in humans.”

The Monograph Programme presents cohort and case-control epidemiological studies of predominately manufacturing and garment industries, as well as mobile homes exposure to formaldehyde containing materials. The data are very much contradictory due to misclassification and inadequate methodology of dose-response relationship. Some dissent studies were partially included 4,5 but some analysts were left out completely 6.

Nasopharyngeal cancer is rare; even one single case that was misclassified on the death certificate (main source of statistic data) can change the entire statistical equation. A simple methodological failure in cohort epidemiological studies cannot be dismissed. A recent analysis of literature data with a title “The enigmatic epidemiology of nasopharyngeal carcinoma” found association of formaldehyde exposure with nasopharyngeal cancer risks unconvincing.7

Nasopharynx, or the nasal part of the pharynx, is a small anatomical area behind the nasal cavity, it is bonded by five walls and borders the oropharynx at the level of lower margin of the uvula. Before formaldehyde reaches the nasopharynx area, it has to go with the inhaled air a long way that is designed to contain any “intruder”. The nasopharynx and nasal cavity communicate through the conches. It is doubtful that formaldehyde specifically targets this relatively small area living alone nasal cavity and pharynx. However, if (IF remains) the IARC conclusion is correct, this location can have some explanation and most importantly open some opportunities for prevention.

Leukemia

 “In summary, there is strong but not sufficient evidence for a casual association between leukemia and occupational exposure to formaldehyde. Increased risk for leukemia has consistently been observed in studies of professional workers and in two of three of most relevant studies of industrial workers.”

Most recent epidemiological studies completely ignore leukemia as a formaldehyde exposure related cause of death among industrial workers.8 For lymphhematopoietic neoplasm there were modestly elevated risks in professional group as pathologists and anatomist.9 The professional group requires special discussion that will be presented below.

Sinonasal cancer 

“Almost all of the formaldehyde-exposed cases in the case -control studies were also exposed to wood dust, which resulted in a high relative risk, particularly for adenocarcinoma. Thus, there is only limited epidemiological evidence that formaldehyde causes cancer in humans.”

The nasal cavity and sinuses are the formaldehyde exposure frontiers. Formaldehyde rarely reaches even sinuses staying on turbinate which have a great square due to curves. It is a puzzle why the frontiers of formaldehyde exposure do not develop cancer.

Cancer at other sites

A number of studies have found associations between exposure to formaldehyde and cancer at other sites, including the oral cavity, oro- and hypopharynx, pancreas, larynx, lung and brain. However, the Working Group considered that overall balance of epidemiological evidence did not support a causal role for formaldehyde in relation to these other cancers.”

The controversies on this issue reflect a debate in cancer epidemiology literature. 10,11 There are evidence of anatomical and clinical unprofessionalism. Even lung cancer should be discriminate as bronchial (most) and parenchmatose.

Experimental data.

Experimental cancer remains the important convincing issue in assessing formaldehyde as carcinogen. The IARC animal carcenogenity data summary noted that inhalation of formaldehyde by rats “showed evidence of carcenogenity, particularly the induction of squamous-cell carcinomas of the nasal cavities”. Studies showed that administration of formaldehyde in drinking-water to rats showed increased evidence of neoplasm. As the main conclusion: “There is sufficient evidence in experimental animals for the carcenogenity of formaldehyde.”

Perhaps, the experimental data require some reservations in application to formalin exposure in anatomical pathology

First, the dose of exposure (up to 14 ppm!!!!) was completely incomparable with laboratory levels. Tumor incidence was 0% at 2 ppm.12,13 Neoplastic cells proliferation might occur as a result of extreme chronic irritation.

Second, there is difference in neoplasm development even between species (mice and hamsters are resistant). Rats and rabbits are obligate nose breathers.

Third, the nostrils, which the air passes through into the nasal cavity, of all animals, including primates, are directed to the front, while the nostrils of man, in distinction, are directed downward. As a result, the current of inspired air instead of passing straight to the back, like in monkeys, flows upward to the olfactory region and follows a long and arched path to the nasopharynx.

Professional groups

Epidemiologic studies have the strengths of numbers and years of duration but limitations of misclassification and unintentional biases. The main weakness of these studies is that they use mortality data. However, in formaldehyde exposure more interesting and promising would be morbidity analysis. In modern society, equipped with advancements medicine, a death, for example, from a nasal cavity cancer is a health care failure.

Formaldehyde exposure in cohorts epidemiological studies in professional groups are of most interest for anatomical pathology. This group includes pathologists, anatomists, and embalmers. It is predictable, that data in this group regarding formaldehyde’s carcinogenicity are inconclusive as heterogeneous and amorphous in regard to formaldehyde exposure is selection of the group.14 Actually, no further epidemiological study on these professionals groups exposed to formaldehyde has been published since 1994 that was justified owning the substantial changes in type of work as far as formaldehyde exposure is concerned.6

Only embalmers in this heterogenic group can be considered as true formaldehyde prone professionals.No neoplasm was reported statistically significant increase of nasal cavity or sinus, although a statistically significant increase in proportionate mortality rates from neoplasm of the hypopharynx was found.15 The death rates for brain tumors and leukemia were also higher than in a control groups. There was no nasal cavity or sinus neoplasm among surveyed embalmers in New York and California but increase in neoplasm of lymphatic/hematopoietic system and buccal cavity. 16

No excess risk for cancers of the oral cavity and pharynx, sinus and nasal cavity and lung were found with some excess risk for brain cancer 17 and lymphoid/hematopoietic neoplasm that was interpreted as unrelated to formaldehyde exposure.9

 References

1. Council Report. Formaldehyde.  Council on Scientific Affairs. JAMA 1989; 261:1183-1187

2. IARC Press Release No 153, 15 June 2004

3. World Health Organization International  Agency for Research on Cancer IARC Monographs on the Evaluation Carcinogenic Risks on Humans Volume 88 , 2006 Formaldehyde Monographs Programme  http://monographs.iarc.fr/ENG/Monographs/Vol88/index.php

4.  Collins JJ, Acquavella JF, Esmen NA: An Updated Meta-Analysis of Formaldehyde Exposure and Upper Respiratory Tract JOEM, Vol 39, Number 7, July 1997: 639-651

5.  Gardner MJ, Pannett B., Winter PD, Crudas AM.  A cohort study of workers exposed to formaldehyde in the British chemical industry: an update British Journal of Industrial Medicine 1993; 50: 827-834

6. McLaughlin JK. Formaldehyde cancer: a critical review. Int Arch Occup Environ Health (1994) 66: 295-301

7. Chang ET. Adami HO The enigmatic epidemiology of nasopharyngeal carcinoma. Cancer Epidemiol. Biomarkers Prev, 2006; 15 (10); 1765-1977

8. Hauptman M, Lubin JH, Stewart PA, Hayes RB, Blair A: Mortality from solid cancers among Workers in Formaldehyde Industries. American Journal of Epidemiology, 159; (12): 1117-1130

9. C. Bosetti C, McLaughlin JK, Tarone RE, Pira E and La Vecchia C: Formaldehyde and cancer risk: a quantative review of cohort studies through 2006. Annals of Oncology 2008; 19; (1): 29-43

10. Torone RE, McLaughlin JK. Re: “Mortality from Solid Cancers among Workers in Formaldehyde Industries.” Am J Epidemiol 2005 Vol 161, (11): 1089-1090.

11. Hauptman M., Lubin JH, Stewart PA, et al. The Authors Reply. Am J. Epidemiol, 2005; 161 (11): 1090-1091.

12. Kerns WD, Pavkov KL, Donofrio DJ, et al: Carcenogenity of formaldehyde in rats and mice after long-term inhalation exposure. Cancer Res 1983; 43: 4382-4392

13. Rusch GM, Clary JJ, Rinehart WE, et al: A 26-week inhalation toxicity study with formaldehyde in the monkey, rat, and hamster. Toxicol Appl Pharmacol 1983; 68: 329-343

14. Harrington JM, Oakes D: Mortality study of British pathologists 1974 to 1980. Br JIndMed 1984; 41: 188-191

15. Walrath J, Fraumeni JF Jr: Mortality patterns among embalmers Cancer Res 1984; 44: 4638-4641.

16 Hayes RB., Blair A, Stewart PA, et al  Mortality of U.S. embalmers and funeral directors. Am JIndMed 1990; 18: 641-652

17. Levine RJ, Andjelkovich DA, Shaw LK. The mortality of Ontario undertakers and a review of formaldehyde related mortality studies. J Occup Med 1984, 26:760-6.

 

 

 

 

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