Review of the Formaldehyde Assessment in the National Toxicology Program 12th Report on Carcinogens (2014) / Chapter Skim
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2 Review of the Formaldehyde Profile in the National Toxicology Program 12th Report on Carcinogens
2 Review of the Formaldehyde Profile in the National Toxicology Program 12th Report on Carcinogens
Pages 33-65
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From page 33... ...
The committee also reviewed the following sections in the substance profile: properties, use, production, exposure, regulations, and guidelines. As part of its review, the committee determined whether NTP had described and conducted its literature search appropriately, whether the relevant literature identified during the literature search was cited and sufficiently described in the background document, whether NTP had selected the most informative studies in making its listing determination, and whether NTP's arguments supported its conclusion that formaldehyde is known to be a human carcinogen.
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From page 34... ...
Cancer Studies in Humans The committee reviewed the "Cancer Studies in Humans" section in the NTP substance profile and the corresponding sections in the background document. NTP described the search strategy used to identify relevant epidemiologic studies, and the committee judged the choice of substance-specific and topicspecific terms to be reasonable.
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From page 35... ...
The study was not informative on the question of an association between formaldehyde and nasopharyngeal or sinonasal cancers because of low statistical power. If the cohort had experienced the mortality rates of the general population in the United States, not even one nasopharyngeal cancer death would have been expected in a population of this size.
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From page 36... ...
The committee concluded that NTP did a thorough job of describing the epidemiology literature in the background document and synthesizing information about key studies in the substance profile. However, the substance profile was not transparent about how the epidemiology evidence met the RoC listing criteria.
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From page 37... ...
NTP based its evaluation of epidemiologic evidence of nasopharyngeal cancer on several lines of evidence. The committee reviewed the background document and the findings of a previous expert panel (McMartin et al.
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From page 38... ...
No other important confounders were identified in the available studies. Lymphohematopoietic Cancer The committee reviewed the background document (NTP 2010)
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From page 39... ...
NTP determined that the most informative studies for evaluating formaldehyde exposure and myeloid leukemia specifically were the British cohort of industrial workers (Coggon et al.
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From page 40... ...
Cancer at Other Tissue Sites The substance profile discusses cancer at other sites only briefly, so the committee's assessment of this section is based on the review in the background document (which is also brief but more informative) and a review of some of the primary literature.
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From page 41... ...
, but it did not find other important or informative animal carcinogenesis studies that were missed by NTP and should have been included in the background document or in the substance profile. It found a few early studies of low power (small numbers of animals were used)
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From page 42... ...
During the first week of the study, the nasal mucosa of some rats was severely damaged by electrocoagulation. A higher nasal-tumor incidence was observed in exposed rats that had damaged nasal epithelium than in rats that had undamaged nasal epithelium, although the study of rats with undamaged epithelium had smaller groups (this was not noted in the background document)
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From page 43... ...
The committee agrees with the inclusion of the studies because they support the overall sufficiency of evidence of carcinogenicity in animals exposed to formaldehyde. One chronic study in female Sprague Dawley rats was not cited in the substance profile and was discounted in the background document because of small groups (Holmström et al.
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From page 44... ...
None of the high-dose animals survived to the end of the study. The background document describes well the series of drinking-water experiments conducted by Soffritti et al.
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From page 45... ...
. Multiple tissue types: NTP cites studies that showed malignancies of the nasal epithelium (mostly squamous-cell carcinomas)
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From page 46... ...
Studies on Mechanisms of Carcinogenesis The section "Studies on Mechanisms of Carcinogenesis" in the substance profile and the associated sections in the background document describe the scientific evidence and mechanistic knowledge available on the carcinogenicity of formaldehyde. The committee finds that the extent, quality, and interpretation of the mechanistic evidence described in these documents are comprehensive and that the importance of this information for the decision to list formaldehyde as a known human carcinogen is clearly explained.
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From page 47... ...
. An expert panel that reviewed a draft version of the background document stated that two mechanisms are supported by available evidence in sinonasal–pharyngeal regions where inhaled formaldehyde first comes into contact with the mucous layer of the respiratory tract in mammals (McMartin et al.
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From page 48... ...
They include DNA– protein cross-links, DNA cross-links, nucleotide base adducts and mutations, and micronuclei. Although the description of genetic damage in the substance profile mentioned key findings and cited appropriate references, the topic would benefit from a clear structure and a clear presentation of the evidence similar to the structure and presentation of evidence in the background document.
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From page 49... ...
The committee points out that the issue of nomenclature of the anatomic structures affected by exposure to formaldehyde is important, and the section would be clearer if the title was revised to make it clear that the information in it pertains to systemic effects of formaldehyde. Overall, the substance profile and background document provide a comprehensive and balanced presentation of the evidence pertinent to the effects of formaldehyde at distal sites.
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From page 50... ...
This section in the substance profile and the corresponding parts of the background document are comprehensive and balanced. The committee finds that the information presented in the substance profile agrees with that presented in the background document.
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From page 51... ...
. The background document and substance profile also note that toxicity of formaldehyde has been reported to occur in the liver, testes, central nervous system, and other organs that would suggest a systemic effect.
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From page 52... ...
Supporting and critical literature are mentioned appropriately in the background document and substance profile. Because this section does not bear on the listing of formaldehyde and because there is no direct evidence of the mechanisms, the review of the literature and the discussion are appropriately brief.
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From page 53... ...
, and various polymers of eight to 100 formaldehyde units that form paraformaldehyde. USE The section "Use" of the substance profile and related background document provide a comprehensive review of industrial uses of formaldehyde and paraformaldehyde.
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From page 54... ...
However, it seems to show that some biomarkers distinguish between exposed and nonexposed workers when the exposure is high enough. The committee observed that the purpose of the section "Exposure" in the background document was not to critically evaluate the industrial exposures that were present for epidemiologic studies evaluated in the section "Cancer Studies in Humans".
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From page 55... ...
REVIEW OF NTP'S LITERATURE-SEARCH METHODS NTP conducted several literature searches to identify carcinogenicity studies that inform the assessment of formaldehyde in the NTP 12th RoC, and some of that information is presented in the section "Human Cancer Studies" of the background document (NTP 2010)
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Tumor SOS response Tumor Tumorigenic* Workers Text words Chromosom*
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SUGGESTED REVISIONS FOR FUTURE EDITIONS OF THE FORMALDEHYDE LISTING IN THE REPORT ON CARGINOGENS Through its review of the background document and substance profile for formaldehyde, the committee identified several revisions that could be made to improve the formaldehyde listing in future iterations of the RoC (see Table 2-2)
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From page 58... ...
Restructure the discussion in the substance profile to parallel the presentation of information in the background document.
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From page 59... ...
Make it clear that the section on "Other Potential Mechanisms of Formaldehyde-induced Leukemia" is intended to show feasibility, not evidence of or support for the mechanisms. Change the title of the section "Hematotoxicity" to "Hematologic and Immunologic Effects" so that the substance profile is consistent with the background document.
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From page 60... ...
2010. Epidemiological studies of formaldehyde exposure and risk of leukemia and nasopharyngeal cancer: A meta-analysis.
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1986. Cancer of the nasal cavi ty and paranasal sinuses, and formaldehyde exposure.
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From page 62... ...
2010. Part A – Peer Review of the Draft Background Document on Formaldehyde.
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1984. Oc cupational formaldehyde exposure and increased nasal cancer risk in man.
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1980a. Induc tion of squamous cell carcinomas of the rat nasal cavity by inhalation exposure to formaldehyde vapor.
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2010. Occupational exposure to for maldehyde, hematotoxicity and leukemia-specific chromosome changes in cul tured myeloid progenitor cells.
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