Review of the Environmental Protection Agency's Draft IRIS Assessment of Formaldehyde (2011) / Chapter Skim
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3 Toxicokinetics and Modes of Action of Formaldehyde
3 Toxicokinetics and Modes of Action of Formaldehyde
Pages 29-63
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From page 29... ...
The committee also reviews EPA's use of the computational pharmacokinetic models and BBDR models that have been developed for formaldehyde and considers EPA's analysis of the sensitivity of low-dose BBDR-model estimates to small changes in model design or model inputs. The discussion provided here is not intended to be exhaustive but rather focuses on the evidence presented in the draft IRIS assessment that was used to support EPA's key conclusions.
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From page 30... ...
Overall, the committee found that the chapters describing the toxicokinetics, modes of action, and various models are well organized and that the draft IRIS assessment accurately reflects the current understanding of the toxicokinetics of inhaled formaldehyde and provides a thorough review of the metabolism, cytotoxicity, and genotoxicity of formaldehyde. The literature review in the draft IRIS assessment appears to be up to date and to include all major and recent studies published as of the release date.
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From page 31... ...
The draft IRIS assessment provides an extensive and thorough review of the literature on the fate of formaldehyde in the body. Formaldehyde is highly water-soluble and exists in water almost exclusively in a reversible hydrated form (methanediol)
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From page 32... ...
Some inhaled formaldehyde passes through the mucus layer to reach the epithelium where its transformation and removal occur by enzymatic reactions with the nasal tissue and nonenzymatic reactions with glutathione and macromolecules, including proteins and DNA. FIGURE 3-1 Schematic representation of the mammalian nasal epithelium.
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From page 33... ...
However, they did observe non-linear DPX formation in the nasal mucosa at concentrations of 2 ppm or greater. In humans, oral breathing bypasses the uptake in the nasal epithelium; this breathing pattern leads to increased delivery of formaldehyde to the intermediate regions of the respiratory tract (that is, from the oral cavity to the upper conducting airways of the lungs)
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From page 34... ...
. The draft IRIS assessment accurately summarizes the main conclusions reached from those experiments, namely that "labeling in the nasal mucosa was due to both covalent binding and metabolic incorporation," that "DPX [were]
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From page 35... ...
EPA also suggested that systemic delivery of formaldehyde-glutathione adducts and latter release of free formaldehyde may result in delivery of formaldehyde to sites distal to the respiratory tract. However, experimental data supporting that hypothesis are lacking, as acknowledged by the draft IRIS assessment.
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From page 36... ...
At identical exposures, mice were found to receive a lower effective dose at the target tissue in the nasal cavities than rats because mice have a greater reduction in minute ventilation in response to sensory irritation of the respiratory tract. The lower effective dose of mice was verified by the observation that mice had smaller increases in formaldehyde-induced cell proliferation in the nasal mucosa than rats.
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From page 37... ...
appear more complicated and reflect a balance between DPX formation and repair processes. Overall, DPX have been detected in upper and lower respiratory tracts of rodents and nonhuman primates.
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From page 38... ...
. The committee agrees with the use of DPX as a biomarker of exposure in the draft IRIS assessment.
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From page 39... ...
Although studies in humans showed some inconsistent results regarding the extent and form of the cytogenetic changes associated with formaldehyde exposure, the overall body of evidence suggests that inhaled formaldehyde has an effect that may be detected in blood cells in the systemic circulation. The committee notes that it is unknown whether formaldehyde genotoxicity arises from interactions that occur at the site of contact -- for example, in nasal-associated lymphoid tissue in the nasal mucosa (Figure 3-1)
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From page 40... ...
. Mass-transfer coefficients calibrated against total nasal uptake were used as boundary conditions in CFD models to determine site-specific formaldehyde flux rates (Kimbell et al.
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From page 41... ...
; any No data exist for comparing site-specific fluxes of formaldehyde with changes to these calculations would result in altered model results (model resolution is substantially greater than experimental flux determinations resolution) ; model evaluations were based on secondary or downstream biomarkers of dose, such as cell proliferation, and lesion-mapping flux rates on the surface can be sensitive to metabolism, reactivity, blood flows, and other mechanisms of tissue clearance (Continued)
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From page 42... ...
, represents mostly methanediol, and it uses the calculated diffusivity the basal membrane, and bone from control rats to constant for methanediol rather than free formaldehyde in simulations of develop the model for respiratory and transitional nasal mucosa epithelium Metabolism of formaldehyde by formaldehyde dehydrogenase (now known as ADH3) and other aldehyde dehydrogenase enzymes was described with a single empirical term because no data existed to differentiate the rates in vivo Abbreviations: CFD, computational fluid dynamics; PK, pharmacokinetic; DPX, DNA-protein crosslinks; BBDR, biologically based dose-response; and ADH3, alcohol dehydrogenases.
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From page 43... ...
The draft IRIS assessment raises the criticism that the nasal CFD models are based on a single geometry for each species. Thus, the models do not address variability that arises from differences in airway anatomy.
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From page 44... ...
Therefore, the committee recommends that the CFD-based approach also be used to extrapolate to low concentrations, that the results be included in the overall evaluation, and that EPA explain clearly its use of CFD modeling approaches. The committee concludes that sufficiently robust pharmacokinetic models for formaldehyde exist and agrees with EPA that the CFD models can and should be used in the IRIS assessment.
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From page 45... ...
Furthermore, no tumors were observed at concentrations that did not also cause cytotoxicity. The draft IRIS assessment discusses this alternative mode of action but relies on the mutagenic mode of action to justify lowdose linear extrapolations in the assessment of formaldehyde-induced nasal tumors.
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From page 46... ...
The local tissue concentration is determined from CFD-derived formaldehyde flux rates, the thickness of the epithelium, and saturable metabolism and first-order clearance from the tissue. DPX concentrations are calculated by assuming firstorder rates of binding to DNA and first-order rates of repair of DPX (thus, the low-dose linear relationship with exposure and higher than linear increase in DPX at concentrations above saturable metabolism by alcohol dehydrogenases)
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From page 47... ...
, they believed that they made conservative choices -- use of the hockey-stick model for cell proliferation rather than the best-fit J-shaped model and steady-state inhalation formaldehyde flux rates and oronasal breathing under various working conditions as the internal dose driver rather than realistic cyclic breathing rates. A major strength of the human model is that its developers were consistently clear about the model structures, the assumptions used to simplify an otherwise complicated process, and how the model parameters were measured, fixed on the basis of relevant data or known system constraints, or estimated from in vivo data.
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From page 48... ...
. Nasal blood flow Blood flow in the nasal The presence of albumin and Explicitly define regional nasal blood submucosa was not considered hemoglobin adducts suggests that flow in the model and determine its in the development of the BBDR formaldehyde can penetrate into the sensitivity to current parameter estimates.
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From page 49... ...
Although that Conolly et al. The simulations should formaldehyde exposure considered more conservative model provided a better description be compared with the EPA default because it removed the low-dose of the data, its application in the no-threshold low-dose extrapolation decrease in cell proliferation and BBDR models would result in assumption, and the results clearly (Continued)
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From page 50... ...
Formaldehyde flux rates Same assumptions, strengths, and Flux rates were based partly on two See Table 3-1 and previous derived from the CFD weaknesses of the CFD models mass-transfer coefficients (one for refinements in which direct coupling of models used to provide apply to the Conolly et al. models mucus-coated and one for non- PK models as boundary conditions on input into the BBDR (see Table 3-1)
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From page 51... ...
assumed that cytotoxicity-compensatory cell proliferation was the dominant mode of action in predicted tumor responses, they were careful to use an upper bound on values of rat parameters to force the model to calculate additional risk due to other mechanisms, such as mutagenicity. EPA conducted a reanalysis of the Conolly et al.
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From page 52... ...
CFD model Cell proliferation followed a J-shaped Minimal; although the cell-proliferation data suggest a J-shaped dose-response relationship, both a J-shaped dose-response relationship and a hockey-stick model were used in the BBDR models. Human cells were equally sensitive to the Minimal; because the relationships between cell proliferation and simulated formaldehyde flux rates were same internal dose surrogate as rats and were similar in rats and monkeys, it is reasonable to assume that they would be similar in humans.
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From page 53... ...
When mutation rates, cell-division rates, and mutation intensity vary as a function of age (that is, not treated as constants over all ages) , the Hoogenveen solution can lead to more errors than alternative models that respect the nonhomogeneity of the model parameters (Crump et al.
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From page 54... ...
The thickening could conceivably dilute DPX measurements used to calibrate the DPX concentrations in the measured tissues to such an extent that residual concentrations 18 hr after BBDR models exposure are not different from those in naïve animals, and this would affect the determination of DPX clearance rates. Abbreviations: DPX, DNA-protein crosslinks; BBDR, biologically based dose-response; CFD, computational fluid dynamics; EPA, Environmental Protection Agency; and MVK, Moolgavkar-Venzon-Knudson.
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From page 55... ...
The committee agrees with EPA that existing data are insufficient to establish the potential biologic variability in model parameters associated with the mutagenic mode of action adequately. However, because the mutagenic mode of action is the major reason for adopting the default low-dose linear extrapolation methods over application of the BBDR models in the draft assessment, the committee recommends that the manipulations that lead to such high contributions of mutagenicity to the mode of action for nasal tumors be reconciled with the observations that formaldehyde is endogenous, that nasal tumors are very rare in both rats and humans, and that no increases in tumor frequency have been observed in animal studies at formaldehyde exposure concentrations that do not also cause cytotoxicity.
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From page 56... ...
The committee also acknowledges that the draft IRIS assessment provides a thorough review of the BBDR models, the major assumptions underpinning the extrapolation to humans, and EPA's own series of papers that evaluated the sensitivity of the BBDR models to these assumptions even though the committee may not agree with the validity of all the resulting manipulations. Should the Biologically Based Dose-Response Models Be Used in the Environmental Protection Agency Quantitative Assessment?
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From page 57... ...
The committee was also struck by the relative lack of transparency in the draft IRIS assessment's description of the decision to use the peer-reviewed BBDR models minimally. The Conolly et al.
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From page 58... ...
Conolly and co-workers felt that they made several conservative assumptions in their models -- use of hockey-stick rather than J-shaped models for cell proliferation, use of overall respiratory tract cancer incidence in humans to calculate basal mutation rates, and use of an upper bound on the proportionality parameter relating DPX to mutation. EPA pushed that concept further by making even more conservative assumptions within the models that cumulatively resulted in radical departures from the results of the Conolly et al.
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From page 59... ...
However, cytotoxicity and compensatory cell proliferation also appear to play important roles in formaldehyde-induced nasal tumors. Although the draft IRIS assessment discusses that mode of action, it relies on the mutagenic mode of action to justify low-dose extrapolations.
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From page 60... ...
1991. Covalent binding of inhaled formaldehyde to DNA in the respiratory tract of rhesus monkeys: Pharmacokinetics, rat-to-monkey interspecies scaling, and extrapolation to man.
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From page 61... ...
2004. Human respiratory tract cancer risks of inhaled formaldehyde: Dose-response predictions derived from biologically motivated computational modeling of a combined rodent and human dataset.
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From page 62... ...
2001a. Dosimetry modeling of inhaled formaldehyde: Comparisons of local flux pre dictions in the rat, monkey, and human nasal passages.
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From page 63... ...
2001. Dosimetry modeling of inhaled for maldehyde: The human respiratory tract.
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