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- Appendix 5 Conceptual Framework for Considering Mode-of- Action of Chemical Carcinogenesis of Formaldehyde
- Postulated mode of action
- Dose-response relationship
- Strength, consistency and specificity of association of tumour response with key events
- Biological plausibility and coherence
- Assessment of postulated mode of action
- Uncertainties, inconsistencies and data gaps
Appendix 4GHS ClassificationIn this report, formaldehyde has been classified against the NOHSC Approved Criteria for Classifying Hazardous Substances (NOHSC, 2004) (see Section 12). The hazard classification of formaldehyde using the GHS classification system is presented in Table A4-1. This system is not mandated in Australia and carries no legal status, but is presented for information purposes. GHS classification and information documentation is available at http://www.unece.org/trans/danger/publi/ghs/ghs_rev01/01files_e.html. Table A4-1: GHS classification for health and environmental hazards of formaldehyde Hazards Classification Hazard communication Health hazard Acute toxicity Symbol: Skull and cross bones Signal word: Danger Hazard statements: Oral Category 3 Toxic if swallowed Dermal Category 3 Toxic in contact with skin Inhalation Category 2 Fatal if inhaled Corrosion/Irritation (Skin & Eye) Category 1 Symbol: Corrosion Signal word: Danger Hazard statements: Causes severe skin burns and eye damage
Sensitisation Symbol: Exclamation mark Signal word: Warning Hazard statements: Skin Category 1 May cause an allergic skin reaction Carcinogenicity Category 1B Symbol: Health hazard Signal word: Danger Hazard statements: May cause cancer by inhalation Environmental hazard Acute toxicity Crustaceans Category 2 Symbol: No symbol is used Signal word: No signal word is used Hazard statements: Toxic to aquatic life Appendix 5Conceptual Framework for Considering Mode-of- Action of Chemical Carcinogenesis of FormaldehydeFor Nasal Tumours
The available data indicate that prolonged inhalation exposure to formaldehyde induce tumours in the nasal cavity of rats in a highly non-linear pattern. Sharp increases in tumour incidence in the nasal cavity occur at concentrations greater than 6 ppm (7.2 mg/m3) formaldehyde. Exposure to concentrations of 2 ppm (2.4 mg/m3) and lower induced no malignant nasal tumours. Results from several epidemiological studies of occupational exposure to formaldehyde have indicated an increased risk of nasopharyngeal cancers, although the data are not consistent. However, while the evidence is not considered to provide sufficient evidence of a causal association, it cannot be entirely excluded from the available data that exposure to formaldehyde may result in the development of nasopharyngeal cancers. This framework analysis will focus on nasal tumours as a result of formaldehyde exposure by inhalation.
The mechanisms by which formaldehyde induces nasal cancers in rats are not fully understood and a specific mechanism to account for this observation has not been identified, especially given that in vivo studies have provided weak or negative evidence of a genotoxic action. However, several lines of evidence suggest a sustained increase in nasal epithelial cell regenerative proliferation resulting from cytotoxicity and mutation marked by DNA-protein crosslinks (DPX), are likely factors contributing to the induction of nasal tumours in rats. Increased cellular proliferation as a consequence of epithelial cell toxicity is the most significant determinant of neoplastic progression. DPX are considered a possible marker of mutagenic potential because they may initiate DNA replication errors that may result in mutation. It is proposed that inhalation of formaldehyde causes inhibition of mucociliary clearance, followed by nasal epithelial cell regenerative proliferation resulting from cytotoxicity and DPX that leads to mutation, and consequent tumour formation. This hypothesis is mainly based on observations of consistent, non- linear dose-response relationships for all three end-points (DPX, sustained increase in proliferation, and tumours) and concordance of the incidence of these effects across regions of the nasal passages.
The key precursor events associated with nasal cancer formation following inhalation exposure to formaldehyde include cytotoxicity and DPX, and nasal epithelial cell regenerative proliferation that are highly non-linear and in concordance with the incidence of nasal tumours. These events have been well defined and measured in a number of studies in rat, monkey, and human epithelial cells.
Available data show a highly non-linear dose-response pattern for the key events, with no observed effects at 2 ppm (2.4 mg/m3), a minimal response at 6 ppm (7.2 mg/m3) and a sharp increase at 10 ppm (12.0 mg/m3) and 15 ppm (18.0 mg/m3). Additionally, there is good correlation between key events and regional tumour incidence and tumour sites. There is also evidence that glutathione-mediated detoxification of formaldehyde within nasal tissues becomes saturated in rats at inhalation exposures above 4 ppm (4.8 mg/m3) (Casanova and Heck, 1987), which may also contribute to the non-linearity of the dose- response relationship for formaldehyde-induced DPX formation, epithelial cell proliferation and subsequently nasal tumour at exposures above this level. A number of short-, medium-, and long-term studies on the effect of formaldehyde exposure on cell proliferation within the respiratory epithelium of rats has indicated a sustained increase in proliferation of nasal epithelial cells following exposure to concentrations greater than 2 ppm (2.4 mg/m3), irrespective of the exposure period. Cell proliferation was observed in animals exposed to formaldehyde from as short as 3 days. In a well-conducted 2-year study in rats with interim kills at 3, 6, 12, and 18 months (Monticello et al. 1996), the magnitude of increased cell proliferation generally decreased over time but still remained significantly increased over controls up to and including the 18 months observation period when this effect was last examined. Data relating to temporal associations for DPX are not of good quality as most available inhalation studies regarding formaldehyde-induced DPX are short-term studies (i.e. exposure duration up to 1 day). Formaldehyde-induced DPX in the nasal epithelium of rats and monkeys were consistently revealed across these studies. However, a well- conducted study investigating acute and cumulative DPX yields in rats exposed to formaldehyde for about 12 weeks (Casanova et al., 1994) found that the acute DPX yield in the lateral meatus was about half that in controls at concentrations greater than 6ppm (7.2 mg/m3). Results of cumulative DPX yields indicated that no significant cumulation of DPX occurred in exposed rats.
There are extensive studies investigating formaldehyde-induced carcinogenicity in both animals and humans. Available data revealed formaldehyde-induced DPX formation and increased epithelial cell proliferation within the upper respiratory tract in a range of animal species including rats and monkeys and a variety of rat and human cells in vitro. It was found that at similar levels of exposure, concentrations of DPX were approximately an order of magnitude less in monkeys than in rats. Increased human epithelial cell proliferation following in situ exposure to formaldehyde was also reported using a model system in which rat trachea populated with human tracheobronchial epithelial cells were xenotransplanted into athymic mice. In addition, proliferative response and increased DPX are seen in regions of the nasal cavity similar to those where tumours have been observed. The highly non-linear dose- response relationships for DPX, cytotoxicity, proliferative response and tumours are consistent, with significant increases in all end-points being observed at concentrations of greater than 4 ppm (4.8 mg/m3). This is also in good correlation with the concentration at which mucociliary clearance is inhibited and glutathione-mediated metabolism saturated i.e., 4 ppm (4.8 mg/m3). The study by Morgan et al. (1986) examining effects of inhaled formaldehyde on the nasal mucociliary apparatus in male rats also included 18 hr recovery groups following day 1, 9 and 14 of exposure to concentrations of 2 (2.4 mg/m3), 6 (7.2 mg/m3) and 15 ppm (18.0 mg/m3). Inhibition of mucociliary clearance was progressively more extensive with increasing duration of exposure but showed little or no evidence of recovery 18 hr after cessation of exposure.
There is a growing body of evidence supporting the biological plausibility that prolonged regenerative cell proliferation can be a causal mechanism in chemical carcinogenesis (IPCS, 2002). The hypothesised mode of action for formaldehyde–induced nasal tumour in animals exposed by inhalation is consistent with the biological plausibility, although the respective roles of DPX, mutation, and cellular proliferation in the induction of tumours in the rat nose are not fully outlined. DPX are proposed to be able to cause mutations as a result of errors of DNA replication on the damaged template. At low doses of formaldehyde, low frequency of DPX was induced and the DNA replication rate will be the normal rate of cell turnover that lead to a very low to negligible mutation frequency. However, at higher doses of formaldehyde when cytotoxicity is induced, the probability of a DPX resulting in a mutation via DNA replication is much higher. The dose-response curve for mutations will be highly non-linear. Thus, the mode of action for tumour induction at higher doses is different from that at low concentrations because of involvement of regenerative cell proliferation. Association of the mode of action for nasal tumours with that for other toxicological end points has been demonstrated in repeated dose toxicity. Sustained increased cell proliferation has been observed in the nasal cavity in extensive short- and medium-term toxicity studies in rats and a few studies in other species. Histopathological effects in the nasal cavity (epithelial cell dysplasia and metaplasia) were consistent in a range of subchronic and chronic animal studies.
Based on the available data, including limited evidence for a direct genotoxic action, it is not possible to identify a further mode of action that could potentially account for the observed nasal tumours.
Based on the weight of evidence, the hypothesized mode of action for formaldehyde- induced nasal tumours satisfies several criteria, including consistency, concordance of dose–response relationships across all key events, and biological plausibility and coherence of the database. Given the extensive experimental data that addresses the mechanisms of formaldehyde-induced tumours in the nasal cavity, a moderate degree of confidence may be ascribed to the above hypothesis.
Uncertainties exist for the proposed mode of action for formaldehyde-induced tumours. In most of the cancer bioassays, data on intermediate end-points, such as proliferative response as a measure of cytotoxicity and DPX, is limited. Consequently, direct comparison of the incidence of intermediate lesions and tumours is restricted. Additionally, information on a direct relationship between DPX and mutation induction and the probability of converting a DPX into a mutation is desirable, while the mode by which regenerative cell proliferation is involved in the production of mutations required for tumour development needs to be determined. Relevance to humans Because formaldehyde is highly reactive at the site of contact, it is critical to take dosimetry into consideration when extrapolating across species. Humans and other primates are oronasal breathers whereas rats are obligate nose breathers. Together with significantly different anatomical features of the nasal and respiratory passages and patterns of inhaled airflow, effects associated with the inhalation of formaldehyde in humans are likely to be observed in a larger area, including deeper parts of the respiratory tract. This is supported by the effects (histopathological changes, increased epithelial cell proliferation, and DPX formation) being observed further along the upper respiratory tract in monkeys, compared to similar effects being restricted to the nasal cavity in rats exposed to moderate levels of formaldehyde. The postulated mode of action on formaldehyde-induced tumours is likely relevant to humans based on the weight of evidence, at least qualitatively. In addition, increased cell proliferation and DPX formation within epithelia of the upper respiratory tract have been observed in monkeys exposed to formaldehyde vapour. Moreover, increased human epithelial cell proliferation following in situ exposure to formaldehyde has also been observed in a model system in which rat trachea populated with human tracheobronchial epithelial cells were xenotransplanted into athymic mice. Direct evidence on histopathological lesions in the nose of humans exposed primarily to formaldehyde in the occupational environment is consistent with a qualitatively similar response of the upper respiratory tract in experimental animals, although this is not sufficient as a basis for inferring causality in itself. While the epidemiological studies do not provide sufficient evidence for a causal association between formaldehyde exposure and human cancer, the possibility of increased risk in humans of respiratory cancers, particularly those of the upper respiratory tract, cannot be excluded on the basis of available data. For Leukaemia
Increased risks for leukaemia, occasionally significant, have been seen in some epidemiology studies in industrial workers. A recent update of a major cohort study reported an association for leukaemia, specifically myeloid leukaemia, and formaldehyde. A reanalysis of the data using additional analysis provided little evidence to support the suggestion of a casual association. Similarly, although increased risks of leukaemia have been observed more consistently in studies of professional workers (e.g. embalmers), it cannot be excluded that observed increases are related to occupational exposures other than formaldehyde. No increased incidence of leukaemia was reported in rodent inhalation studies. An increased incidence of haemolymphoreticular tumours (i.e. leukaemias and lymphomas combined) was reported in a single questionable drinking water study in the rat. This framework analysis will focus on leukaemia as a result of formaldehyde exposure by inhalation in humans and ingestion in rats.
A mode of action by which formaldehyde may induce leukaemia has not been identified. Although the possibility of transforming mutations to stem cells has been proposed in the scientific literature as a mechanism for leukaemia (Reya et al., 2001) there is currently no experimental data with formaldehyde to support this proposal. While the detection of cytogenetic abnormalities in circulating lymphocytes of workers exposed to formaldehyde might be regarded as supporting such a possibility, such effects have not been consistently observed and co-exposure to other chemicals means that it cannot be reliably concluded that they were caused by formaldehyde. Furthermore, there is only limited evidence suggesting a weak direct genotoxic action in in vivo studies in rodents. Therefore, presently, there is insufficient evidence to support the postulation that formaldehyde- induced leukaemia occurs from mutations to stem cells.
There is presently no experimental data that addresses the mechanism of formaldehyde- induced leukaemia. Consequently, the key precursor events associated with the induction of leukaemia following exposure to formaldehyde have not been defined in animal or human studies.
Although an increased incidence in haemolymphoreticular tumours was reported in a single questionable drinking water study in the rat the increase was not dose-related. Furthermore, the pooling of tumour types reported as leukaemias and lymphomas prevents the dose-response relationship for leukemia to be specifically determined. In humans, an increased risk of leukaemia, occasionally significant, has been inconsistently reported in human epidemiology studies. Nearly all of these studies estimated exposure levels. The available data do not allow construction of a reliable dose-response relationship for formaldehyde exposure and incidence of leukaemia.
No key events have been identified in human or animal studies for formaldehyde-induced leukaemia, consequently, an analysis of potential temporal associations cannot be undertaken.
There are extensive studies investigating formaldehyde-induced carcinogenicity in both animals and humans. In human epidemiology studies, an increased risk of leukaemia has not been consistently observed, while in rodent studies a single, questionable oral study reported an increase incidence in haemolymphoreticular tumours. No increased incidence of leukaemia was reported in two further oral studies or inhalation studies in rodents. No key events have been identified in human or animal studies for formaldehyde-induced leukaemia.
The available data, such as the toxicokinetic profile for formaldehyde, does not support the biological plausibility of formaldehyde-induced leukaemia. No increase in formaldehyde concentration was seen in blood in humans and rats following exposure to concentrations of 1.9 ppm (2.3 mg/m3) and 14.4 ppm (17.3 mg/m3) formaldehyde, respectively. This has been attributed to the rapid metabolism of formaldehyde. Such rapid metabolism would inhibit systemic distribution of formaldehyde. This is supported by the absence of an effect on the bone marrow in subchronic rodent studies, and the absence of leukaemia in several inhalation bioassays and two drinking water bioassays in rodents. Furthermore, with the exception of a single, questionable, non-standard in vivo study, negative results were seen in several bone marrows cytogenetic and micronuclei studies conducted to validated test methodology. Thus, while inconsistent results of an increased risk of leukaemia have been seen in epidemiology studies and there is limited and questionable evidence from animal studies supporting the possibility of leukaemia, there are numerous negative findings in animal studies that do not support such a possibility. Toxicokinetic information suggests that following absorption formaldehyde would not reach distal sites. Overall, the available data do not support formaldehyde being leukemogenic.
No experimental data that addresses the mechanism of formaldehyde-induced leukaemia are available and, hence, no mode of action has been postulated.
No postulated mode of action has been proposed. However, from the available data formaldehyde-induced leukaemia do not satisfy several criteria, including consistency, and biological plausibility and coherence of the database. Consequently, a low degree of confidence may be ascribed to the hypothesis that formaldehyde induces leukaemia.
No experimental data that addresses the mechanism of formaldehyde-induced leukaemia is available and, hence, no mode of action has been proposed. Furthermore, increased incidences of leukaemia have been inconsistently observed in epidemiology studies. Similarly, while there is a large database for testing in animals, a non dose-related increased incidence of leukaemia and lymphomas combined has only been reported in a single questionable drinking water study in the rat. However, it should be noted that the absence of clear evidence of bone marrow toxicity in humans and animals indicates that if formaldehyde is a human myeloid leukogen its mode of action is likely to be different from known myeloid leukogens (such as benzene). Consequently, the absence of findings of leukaemia in the animal studies would suggest that a reliable rodent model for formaldehyde-induced myeloid leukaemia is not presently available. Relevance to humansNo postulated mode of action has been identified. The available human and animal data do not satisfy several criteria, including consistency, and biological plausibility and coherence, for formaldehyde being leukaemogenic. ReferenceReya, T, Morrison, S, Clarke, MF and Weissman, IL (2001). Stem cells, cancer, and cancer stem cells (2001). Nature, 414, p105 – 111. Directory: data -> assets -> word doc -> 0006 word doc -> Commonwealth of Australia 2002 word doc -> Commonwealth of Australia 2000 word doc -> Priority Existing Chemical word doc -> Rail safety news issue 6 – October 2011 word doc -> Review of Multiple Chemical Sensitivity: Identifying 0006 -> Board Endorsed October 2009 amended 13-09-11 with extra units 0006 -> Rt Hon Andrew Lansley cbe mp secretary of State for Health 0006 -> Environmental Approvals Application Form Use this form Download 5.77 Mb. Share with your friends:
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