In vitro skin penetration of bronidox, bronopol and formaldehyde from cosmetics.

The objective was to evaluate the influence of the formulation in the in vitro transdermal absorption through pig ear skin of three preservatives, bronopol, bronidox and formaldehyde as well as the absorption of formaldehyde from bronopol and dimethyloldimethyl hydantoin (DMDM hydantoin). An aqueous solution, an O/W emulsion and a hydrogel were assayed. Bronidox and bronopol absorption depends on the formulation. The O/W emulsion was the system that least promoted absorption of bronidox while the absorption of bronopol was lower from the hydrogel. The aqueous solution provided maximal transdermal absorption of both preservatives. Moreover, the transdermal absorption of formaldehyde released from bronopol also depends on the formulation, being the aqueous solution the system that allowed greater absorption. Transdermal absorption of formaldehyde, applied directly or released from DMDM hydantoin, is not conditioned by the excipients. The degree of transdermal absorption of all the preservatives tested is low and therefore the concentrations allowed by regulations are safely used. Nonetheless, since formaldehyde was detected in the receptor compartment after a long time exposure to bronopol and DMDM hydantoin it would be important to consider the possibility of limiting the use of these two preservatives to rinse off products as is the case of bronidox.

Formalin pigment artifact deposition in autopsy tissue: predisposing factors, patterns of distribution and methods for removal.

Formalin pigment deposition is a known artifact of autopsy histology, often anecdotally associated with decomposition of bodies. However, there is minimal data within the forensic literature demonstrating an association between formalin pigment deposition and length of postmortem interval. Furthermore, there is minimal data concerning other predisposing factors and patterns of distribution of formalin pigment deposition. In this study, we compare the amount and patterns of formalin deposition on histology slides from three categories of death: 1) decomposed bodies, 2) critically ill at time of death, and 3) sudden cardiac death. We also compare the effectiveness of two relatively simple histology laboratory methods to remove formalin pigment deposition from histology slides. Amongst the three categories of death, formalin deposition was highest in the decomposed category, second highest in the critically ill category, and lowest in the sudden cardiac death category. The organs most severely affected by formalin deposition were liver/spleen/pancreas and kidneys, and the organs least affected were brain and lung. Formalin pigment deposition correlated with length of postmortem interval. Histologic patterns of formalin deposition included the endothelial lining of vessels, perinuclear compartment of neurons and myocytes, and the basal epithelial compartment of renal tubular epithelial cells. The alcoholic ammonium hydroxide method (AAH) was slightly more effective than the alkylphenol ethoxylate (APE) method for removing formalin pigment, though both methods were effective. Because formalin pigment is strongly refractile under polarized light, a polarization filter can also be useful for distinguishing formalin pigment from other pigments.

Topical therapeutic corneal and scleral tissue cross-linking solutions: in vitro formaldehyde release studies using cosmetic preservatives.

Our recent tissue cross-linking studies using formaldehyde releasers (FARs) suggest that corneal and scleral tissue strengthening may be possible without using ultraviolet irradiation or epithelial removal, two requirements for the photochemical method in widespread clinical use. Thus, the present study was carried out in order to better understand these potential therapeutic solutions by studying the effects of concentration, pH, buffer, time, and tissue reactivity on formaldehyde release of these FARs. Three FARs, sodium hydroxymethyl glycinate (SMG), DMDM, and diazolidinyl urea (DAU) were studied using a chromotropic acid colorimetric FA assay. The effects of concentration, pH, and buffer were studied as well as the addition of corneal and scleral tissues. The main determinant of release was found to be dilution factor (concentration) in which maximal release was noted at the lowest concentrations studied (submillimolar). In time dependent studies, after 60 min, FA levels decreased by 38% for SMG, 30% for DMDM, and 19% for DAU with corneal tissue added; and by 40% for SMG, 40% for DMDM, and 15% for DAU with scleral tissue added. We conclude that concentration (dilution factor) was found to be the most important parameter governing the percent of FA released.

Estimates of parameters for formaldehyde emission model from plywood panel under various temperature and relative humidity conditions.

The initial emittable concentration, Cm,0, the material phase diffusion coefficient, Dm, and the air/material partition coefficient, K, are the key parameters used to predict the formaldehyde emissions from indoor building materials. This work presents formaldehyde emission experiments of plywood panels in a climatic chamber under various environmental conditions, which provides information on how relative humidity, temperature, and loading degree affect the formaldehyde emission. The experimental results showed that formaldehyde concentration in the climatic chamber increased rapidly during the initial 3 h, and then reached equilibrium after 7 h. The equilibrium concentration of formaldehyde in the closed chamber was increased by 1.1-1.3 times with the relative humidity increased by 20%, and 1.3-2.5 times with the temperature increased by 5 °C, respectively. In agreement with the experimental treatment, a new method of estimating parameters was carried out in a theoretical model from formaldehyde emission, opening the way to a factorial analysis of the relevant parameters for relative humidity and temperature. The theoretical model with estimated parameters was further validated by experiments with different environmental conditions, which should help to quickly determine the parameters needed to predict formaldehyde emissions.

The Effects of Formaldehyde on Cytochrome P450 Isoform Activity in Rats.

Formaldehyde (FA) is an occupational and indoor pollutant. Long-term exposure to FA can irritate the respiratory mucosa, with potential carcinogenic effects on the airways. The effects of acute FA poisoning on the activities of CYP450 isoforms CYP1A2, CYP2C11, CYP2E1, and CYP3A2 were assessed by determining changes in the pharmacokinetic parameters of the probe drugs phenacetin, tolbutamide, chlorzoxazone, and testosterone, respectively. Rats were randomly divided into three groups: control, low FA dose (exposure to 110 ppm for 2 h for 3 days), and high FA dose (exposure to 220 ppm for 2 h for 3 days). A mixture of the four probe drugs was injected into rats and blood samples were taken at a series of time points. Plasma concentrations of the probe drugs were measured by HPLC. The pharmacokinetic parameters t1/2, AUC(0-t), and Cmax of tolbutamide, chlorzoxazone, and testosterone increased significantly in the high dose versus control group (P < 0.05), whereas the CL of chlorzoxazone and testosterone decreased significantly (P < 0.05). However, t1/2, AUC(0-t), and Cmax of phenacetin decreased significantly (P < 0.05), whereas the CL of phenacetin increased significantly (P < 0.05) compared to controls. Thus, acute FA poisoning suppressed the activities of CYP2C11, CYP2E1, and CYP3A2 and induced the activity of CYP1A2 in rats. And the change of CYP450 activity caused by acute FA poisoning may be associated with FA potential carcinogenic effects on the airways.

The bottom-up approach to bounding potential low-dose cancer risks from formaldehyde: An update.

In 2013, we proposed a novel bottom-up approach to bounding low-dose cancer risks that may result from small exogenous exposures to chemicals that are always present in the body as a result of normal biological processes. The approach utilizes the background cancer risk and the background (endogenous) concentration of a cancer-related exposure biomarker in specific target tissues. After allowing for statistical uncertainty in these two parameters, the ratio of the background risk to background exposure provides a conservative slope factor estimate that can be utilized to bound the added risk that may be associated with incremental exogenous exposures. Our original bottom-up estimates were markedly smaller than those obtained previously by the US Environmental Protection Agency (USEPA) with a conventional top-down approach to modeling nasopharyngeal cancer and leukemia mortality data from a US worker cohort. Herein we provide updated bottom-up estimates of risk for these two cancers that are smaller still, and rely upon more robust estimates of endogenous and exogenous formaldehyde-DNA adducts in monkeys and a more robust estimate of the DNA adduct elimination half-life in rats, both obtained very recently. We also re-examine the worker mortality data used by USEPA in developing its estimate of human leukemia incidence from lifetime exposure to 1 ppm airborne formaldehyde. Finally, we compare a new bottom-up slope estimate of the risk of rat nasal cancer with conventional top-down estimates obtained with empirical dose-response modeling of rat nasal cancer bioassay data.

Role of partition coefficients in determining the percutaneous penetration of salicylic acid and formaldehyde under varying occlusion durations.

CONTEXT: Occlusion is widely utilized to enhance the percutaneous penetration of applied drugs in clinical practice; however, occlusion does not increase the penetration of all chemicals. OBJECTIVE: This study determines: (1) whether occlusion enhances the percutaneous penetration of the lipophilic salicylic acid or the hydrophilic formaldehyde when compared to non-occlusion, (2) evaluate whether occlusion duration affects the penetration of compounds and (3) establish to what extent occlusive films in clinical practice interact with topically-applied chemicals and possibly hinder penetration. MATERIALS AND METHODS: Separately, single doses of [14C]-formaldehyde and [14C]-salicylic acid were applied onto human skin overlying diffusion cells under non-occlusion as well as various occlusive time periods (1, 4 and 8 h). The percent dose penetrating into each compartment as well the percent dose adhering to the plastic wrap were determined. RESULTS: The radioactivity recovery as percent of applied dose of [14C]-salicylic acid was significantly higher under occlusion versus non-occlusion in the epidermis, dermis and receptor fluid after 24 h (p < 0.05). For [14C]-formaldehyde, no significant statistical differences were observed between occlusion versus non-occlusion. The plastic wrap often used to enhance the penetration of topically applied drugs does not itself substantially adhere to the tested chemicals. CONCLUSION: Occlusion duration, previously undocumented for in vitro studies, impacted the percutaneous penetration of the lipophilic salicylic acid more so than the hydrophilic formaldehyde. A strong correlation between occlusion-enhanced penetration and partition coefficients was observed, but we do not wish to overgeneralize these results until more compounds of varying physical--chemical properties are studied.

Inhaled formaldehyde induces DNA-protein crosslinks and oxidative stress in bone marrow and other distant organs of exposed mice.

Formaldehyde (FA), a major industrial chemical and ubiquitous environmental pollutant, has been classified as a leukemogen. The causal relationship remains unclear, however, due to limited evidence that FA induces toxicity in bone marrow, the site of leukemia induction, and in other distal organs. Although induction of DNA-protein crosslinks (DPC), a hallmark of FA toxicity, was not previously detected in the bone marrow of FA-exposed rats and monkeys in studies published in the 1980s, our recent studies showed increased DPC in the bone marrow, liver, kidney, and testes of exposed Kunming mice. To confirm these preliminary results, in the current study we exposed BALB/c mice to 0, 0.5, 1.0, and 3.0 mg m(-3) FA (8 hr per day, for 7 consecutive days) by nose-only inhalation and measured DPC levels in bone marrow and other organs of exposed mice. As oxidative stress is a potential mechanism of FA toxicity, we also measured glutathione (GSH), reactive oxygen species (ROS), and malondialdehyde (MDA), in the bone marrow, peripheral blood mononuclear cells, lung, liver, spleen, and testes of exposed mice. Significant dose-dependent increases in DPC, decreases in GSH, and increases in ROS and MDA were observed in all organs examined (except for DPC in lung). Bone marrow was among the organs with the strongest effects for DPC, GSH, and ROS. In conclusion, exposure of mice to FA by inhalation induced genotoxicity and oxidative stress in bone marrow and other organs. These findings strengthen the biological plausibility of FA-induced leukemogenesis and systemic toxicity.

Evaluation of the permeability of formaldehyde and water through a permeation tube for the preparation of an accurate formaldehyde reference gas mixture.

A system for continuous generation and analysis of formaldehyde (HCHO) in a nitrogen gas mixture prepared using a permeation method was fabricated in order to evaluate the permeability of HCHO and water (H2O) through a permeation tube. Specifically, the mass balance of HCHO and H2O through a permeation tube was evaluated using the system. The results indicated that the mass loss in the permeation tube accounted for the amount of HCHO and H2O measured using a spectrometer. The permeability of HCHO was calculated by subtracting the mass loss of H2O from the permeation tube per unit of time as determined from the mass balance results. The calculated permeability of HCHO was 75.7 ± 3.4 mg min(-1) (k = 2) for the HCHO gas mixture prepared by the permeation method using a permeation tube filled with paraformaldehyde that was vacuum-dried at 95 °C. The calculated permeability agreed with the permeability obtained using the dinitrophenylhydrazine-derivatization method (72.7 ± 4.4 mg min(-1) (k = 2)) within the level of uncertainty. This technique, in which the mass loss of H2O from the permeation tube is subtracted, can therefore provide a reference gas mixture with an accurate HCHO concentration using the permeation method.

Pharmacokinetic modeling as an approach to assessing the safety of residual formaldehyde in infant vaccines.

Formaldehyde is a one-carbon, highly water-soluble aldehyde that is used in certain vaccines to inactivate viruses and to detoxify bacterial toxins. As part of the manufacturing process, some residual formaldehyde can remain behind in vaccines at levels less than or equal to 0.02%. Environmental and occupational exposure, principally by inhalation, is a continuing risk assessment focus for formaldehyde. However, exposure to formaldehyde via vaccine administration is qualitatively and quantitatively different from environmental or occupational settings and calls for a different perspective and approach to risk assessment. As part of a rigorous and ongoing process of evaluating the safety of biological products throughout their lifecycle at the FDA, we performed an assessment of formaldehyde in infant vaccines, in which estimates of the concentrations of formaldehyde in blood and total body water following exposure to formaldehyde-containing vaccines at a single medical visit were compared with endogenous background levels of formaldehyde in a model 2-month-old infant. Formaldehyde levels were estimated using a physiologically-based pharmacokinetic (PBPK) model of formaldehyde disposition following intramuscular (IM) injection. Model results indicated that following a single dose of 200 µg, formaldehyde is essentially completely removed from the site of injection within 30 min. Assuming metabolism at the site of injection only, peak concentrations of formaldehyde in blood/total body water were estimated to be 22 µg/L, which is equivalent to a body burden of 66 µg or <1% of the endogenous level of formaldehyde. Predicted levels in the lymphatics were even lower. Assuming no adverse effects from endogenous formaldehyde, which exists in blood and extravascular water at background concentrations of 0.1 mM, we conclude that residual, exogenously applied formaldehyde continues to be safe following incidental exposures from infant vaccines.

A quantitative study of the influence of inhaled compounds on their concentrations in exhaled breath.

Throughout the development of breath analysis research, there has been interest in how the concentrations of trace compounds in exhaled breath are related to their concentrations in the ambient inhaled air. In considering this, Phillips introduced the concept of 'alveolar gradient' and judged that the measured exhaled concentrations of volatile organic compounds should be diminished by an amount equal to their concentrations in the inhaled ambient air. The objective of the work described in this paper was to investigate this relationship quantitatively. Thus, experiments have been carried out in which inhaled air was polluted by seven compounds of interest in breath research, as given below, and exhaled breath has been analysed by SIFT-MS as the concentrations of these compounds in the inhaled air were reduced. The interesting result obtained is that all the exogenous compounds are partially retained in the exhaled breath and there are close linear relationships between the exhaled and inhaled air concentrations for all seven compounds. Thus, retention coefficients, a, have been derived for the following compounds: pentane, 0.76 ± 0.09; isoprene, 0.66 ± 0.04; acetone, 0.17 ± 0.03; ammonia, 0.70 ± 0.13, methanol, 0.29 ± 0.02; formaldehyde, 0.06 ± 0.03; deuterated water (HDO), 0.09 ± 0.02. From these data, correction to breath analyses for inhaled concentration can be described by coefficients specific to each compound, which can be close to 1 for hydrocarbons, as applied by Phillips, or around 0.1, meaning that inhaled concentrations of such compounds can essentially be neglected. A further deduction from the experimental data is that under conditions of the inhalation of clean air, the measured exhaled breath concentrations of those compounds should be increased by a factor of 1/(1 - a) to correspond to gaseous equilibrium with the compounds dissolved in the mixed venous blood entering the alveoli. Thus, for isoprene, this is a factor of 3, which we have confirmed experimentally by re-breathing experiments.

Complicated suicide versus autoeroticism?: a case involving multiple drugs and a porta-potty.

In this report, a unique and bizarre case of complicated suicide is presented. The decedent was found dead in the basin of a porta-potty, wearing women's pantyhose, jewelry, and makeup. The initial investigation was suspect for homicide. Although an autoerotic accidental death cannot be excluded, the patient's medical history and autopsy results provided evidence for suicide, including several substances positive in his serum. Tramadol was quantified to be 140 mg/L, approximately 470 times the therapeutic range. Moreover, formaldehyde was also present, presumably absorbed from the contents of the chemical toilet. An exhaustive search could not reveal similar circumstances of suicide in a porta-potty or with the levels of tramadol found in the decedent.

Accumulated hippocampal formaldehyde induces age-dependent memory decline.

Aging is an important factor in memory decline in aged animals and humans and in Alzheimer's disease and is associated with the impairment of hippocampal long-term potentiation (LTP) and down-regulation of NR1/NR2B expression. Gaseous formaldehyde exposure is known to induce animal memory loss and human cognitive decline; however, it is unclear whether the concentrations of endogenous formaldehyde are elevated in the hippocampus and how excess formaldehyde affects LTP and memory formation during the aging process. In the present study, we report that hippocampal formaldehyde accumulated in memory-deteriorating diseases such as age-related dementia. Spatial memory performance was gradually impaired in normal Sprague-Dawley rats by persistent intraperitoneal injection with formaldehyde. Furthermore, excess formaldehyde treatment suppressed the hippocampal LTP formation by blocking N-methyl-D-aspartate (NMDA) receptor. Chronic excess formaldehyde treatment over a period of 30 days markedly decreased the viability of the hippocampus and down-regulated the expression of the NR1 and NR2B subunits of the NMDA receptor. Our results indicate that excess endogenous formaldehyde is a critical factor in memory loss in age-related memory-deteriorating diseases.

The determination of exogenous formaldehyde in blood of rats during and after inhalation exposure.

Formaldehyde (FA) is suspected of being associated with the development of leukemia. An inhalation experiment with FA was performed in rats to study whether FA can enter the blood and could thus cause systemic toxicity in remote tissues such as the bone marrow. Therefore, a sophisticated analytical method was developed to detect blood concentrations of FA during and after single 6-h exposure by inhalation. In order to differentiate between exogenous and endogenous FA the rats were exposed to stable isotope ((13)C) labeled FA by inhalation. During and after exposure of the rats to (13)C-FA their blood was analyzed to determine the ratio between labeled and natural FA in blood and the total blood concentration of FA. With respect to sensitivity, with the applied method exogenous (13)C-FA could have been detected in blood at a concentration approximately 1.5% of the endogenous FA blood concentration. Exogenous (13)C-FA was not detectable in the blood of rats either during or up to 30 min after the exposure. It was concluded that the inhalation of (13)C-FA at 10 ppm for 6h did not result in an increase of the total FA concentration in blood.

Neonicotinoid formaldehyde generators: possible mechanism of mouse-specific hepatotoxicity/hepatocarcinogenicity of thiamethoxam.

Thiamethoxam (TMX), an important insecticide, is hepatotoxic and hepatocarcinogenic in mice but not rats. Studies of Syngenta Central Toxicology Laboratory on species specificity in metabolism established that TMX is a much better substrate for mouse liver microsomal CYPs than the corresponding rat or human enzymes in forming desmethyl-TMX (dm-TMX), which is also hepatotoxic, and clothianidin (CLO), which is not hepatotoxic or hepatocarcinogenic. They proposed that TMX hepatotoxicity/hepatocarcinogencity is due to dm-TMX and a further metabolite desmethyl-CLO (dm-CLO) (structurally analogous to a standard inducible nitric oxide synthase inhibitor) acting synergistically. The present study considers formation of formaldehyde (HCHO) and N-methylol intermediates as an alternative mechanism of TMX hepatotoxicity/hepatocarcinogenicity. Comparison of neonicotinoid metabolism by mouse, rat and human microsomes with NADPH showed two important points. First, TMX and dm-TMX yield more HCHO than any other commercial neonicotinoid. Second, mouse microsomes give much higher conversion than rat or human microsomes. These observations provide an alternative hypothesis of HCHO and N-methylol intermediates from CYP-mediated oxidative oxadiazinane ring cleavage as the bioactivated hepatotoxicants. However, the proposed mono-N-methylol CYP metabolites are not observed, possibly further reacting in situ.

Recent trend in risk assessment of formaldehyde exposures from indoor air.

Studies about formaldehyde (FA) published since the guideline of 0.1 mg/m(3) by the World Health Organization (WHO) in 2010 have been evaluated; critical effects were eye and nasal (portal-of-entry) irritation. Also, it was considered to prevent long-term effects, including all types of cancer. The majority of the recent toxicokinetic studies showed no exposure-dependent FA-DNA adducts outside the portal-of-entry area and FA-DNA adducts at distant sites were due to endogenously generated FA. The no-observed-adverse-effect level for sensory irritation was 0.5 ppm and recently reconfirmed in hypo- and hypersensitive individuals. Investigation of the relationship between FA exposure and asthma or other airway effects in children showed no convincing association. In rats, repeated exposures showed no point mutation in the p53 and K-Ras genes at ≤15 ppm neither increased cell proliferation, histopathological changes and changes in gene expression at 0.7 ppm. Repeated controlled exposures (0.5 ppm with peaks at 1 ppm) did not increase micronucleus formation in human buccal cells or nasal tissue (0.7 ppm) or in vivo genotoxicity in peripheral blood lymphocytes (0.7 ppm), but higher occupational exposures were associated with genotoxicity in buccal cells and cultivated peripheral blood lymphocytes. It is still valid that exposures not inducing nasal squamous cell carcinoma in rats will not induce nasopharyngeal cancer or lymphohematopoietic malignancies in humans. Reproductive and developmental toxicity are not considered relevant in the absence of sensory irritation. In conclusion, the WHO guideline has been strengthened.

A lung dosimetry model of vapor uptake and tissue disposition.

Inhaled vapors may be absorbed at the alveolar-capillary membrane and enter arterial blood flow to be carried to other organs of the body. Thus, the biological effects of inhaled vapors depend on vapor uptake in the lung and distribution to the rest of the body. A mechanistic model of vapor uptake in the human lung and surrounding tissues was developed for soluble and reactive vapors during a single breath. Lung uptake and tissue disposition of inhaled formaldehyde, acrolein, and acetaldehyde were simulated for different solubilities and reactivities. Formaldehyde, a highly reactive and soluble vapor, was estimated to be taken up by the tissues in the upper tracheobronchial airways with shallow penetration into the lung. Vapors with moderate solubility such as acrolein and acetaldehyde were estimated to penetrate deeper into the lung, reaching the alveolar region where absorbed vapors had a much higher probability of passing through the thin alveolar-capillary membrane to reach the blood. For all vapors, tissue concentration reached its maximum at the end of inhalation at the air-tissue interface. The depth of peak concentration moved within the tissue layer due to vapor desorption during exhalation. The proposed vapor uptake model offers a mechanistic approach for calculations of lung vapor uptake, air:tissue flux, and tissue concentration profiles within the respiratory tract that can be correlated to local biological response in the lung. In addition, the uptake model provides the necessary input for pharmacokinetic models of inhaled chemicals in the body, thus reducing the need for estimating requisite parameters.

Hematological and toxicological evaluation of formaldehyde as a potential cause of human leukemia.

Epidemiological findings suggesting that formaldehyde exposure is associated with a higher risk of acute myelogenous leukemia (AML) and other hematological cancers have led to consideration of the potential mechanism of action by which inhalation of this rapidly reactive agent can cause bone marrow cancer. Two major mechanism-based arguments against formaldehyde as a leukemogen have been the difficulty in envisioning how inhaled formaldehyde might penetrate to the bone marrow; and the lack of similarity of non-cancer effects to other known human myeloleukemogens, particularly the absence of pancytopenia in humans or laboratory animals exposed to high levels. However, both of these arguments have been addressed by the recent finding of a pancytopenic effect and chromosomal abnormalities in heavily exposed Chinese workers which, if replicated, are indicative of a genotoxic effect of formaldehyde on hematopoietic stem cells that is in keeping with other known human leukemogens. Review of the body of evidence suggests an apparent discrepancy between studies in laboratory animals, which generally fail to show evidence of penetration of formaldehyde into the blood or evidence of blood or bone marrow genotoxicity, and studies of exposed humans in which there tends to be evidence of genotoxicity in circulating blood cells. One possible explanation for this discrepancy is species difference. Another possible explanation is that myeloid precursors within the nasal mucosa may be the site for leukemogenesis. However, chloromas, which are local collections of myeloid tumor cells, are rarely if ever found in the nose. Other proposed mechanisms for formaldehyde leukemogenesis are reviewed, and dose issues at the interface between the epidemiological and hematotoxicological findings are explored.

Statistical inferences from formaldehyde DNA-protein cross-link data: improving methods for characterization of uncertainty.

Physiologically based pharmacokinetic (PBPK) modeling has reached considerable sophistication in its application to pharmacological and environmental health problems. Yet, mature methodologies for making statistical inferences have not been routinely incorporated in these applications except in a few data-rich cases. This paper demonstrates how improved statistical inference on estimated model parameters from both frequentist and Bayesian points of view can be routinely carried out. We work with a previously developed PBPK model for the formation and disposition of DNA-protein cross-links formed by inhaled formaldehyde in the nasal lining of rats and rhesus monkeys. We purposefully choose this model because it is based on sparse time-course data.

Formaldehyde: integrating dosimetry, cytotoxicity, and genomics to understand dose-dependent transitions for an endogenous compound.

Formaldehyde (FA), an endogenous cellular aldehyde, is a rat nasal carcinogen. In this study, concentration and exposure duration transitions in FA mode of action (MOA) were examined with pharmacokinetic (PK) modeling for tissue formaldehyde acetal (FAcetal) and glutathione (GSH) and with histopathology and gene expression in nasal epithelium from rats exposed to 0, 0.7, 2, 6, 10, or 15 ppm FA 6 h/day for 1, 4, or 13 weeks. Patterns of gene expression varied with concentration and duration. At 2 ppm, sensitive response genes (SRGs)-associated with cellular stress, thiol transport/reduction, inflammation, and cell proliferation-were upregulated at all exposure durations. At 6 ppm and greater, gene expression changes showed enrichment of pathways involved in cell cycle, DNA repair, and apoptosis. ERBB, EGFR, WNT, TGF-ß, Hedgehog, and Notch signaling were also enriched. Benchmark doses for significantly enriched pathways were lowest at 13 weeks. Transcriptional and histological changes at 6 ppm and greater corresponded to dose ranges in which the PK model predicted significant reductions in free GSH and increases in FAcetal. Genomic changes at 0.7-2 ppm likely represent changes in extracellular FAcetal and GSH. DNA replication stress, enhanced proliferation, squamous metaplasia, and stem cell niche activation appear to be associated with FA carcinogenesis. Dose dependencies in MOA, high background FAcetal, and nonlinear FAcetal/GSH tissue kinetics indicate that FA concentrations below 1 or 2 ppm would not increase risk of cancer in the nose or any other tissue or affect FA homeostasis within epithelial cells.