Assessment of indirect inhalation exposure to formaldehyde evaporated from water.

Volatilization volumes and health risks associated with indirect inhalation exposure to formaldehyde evaporated from water have not been investigated quantitatively. We experimentally investigated formaldehyde volatility, compared with chloroform volatility, predicted formaldehyde inhalation exposure concentrations in Japanese bathrooms, and then re-evaluated drinking water quality standards. Although the Henry's law constant of formaldehyde is 1/104 that of chloroform, with a 30-min exposure period, the formaldehyde non-equilibrium partition coefficient (K'd) was 1/500th the chloroform value because of formaldehyde's faster volatilization rate. We used this ratio to estimate the cumulative probability distribution of formaldehyde concentrations in bathroom air. For a formaldehyde concentration in water of ≤2.6 mg/L-water (WHO tolerable concentration), the probability that the incremental formaldehyde concentration due to volatilization would exceed 100 µg/m3-air (WHO indoor air quality guideline) was low. However, major sources of formaldehyde in indoor air are building materials and furniture. We therefore calculated the allowable concentration in water by allocating a small percentage of the indoor air guideline value to indirect inhalation exposure via volatilization from tap water. With an allocation factor of 20% (10%), the allowable concentration was 0.52 (0.26) mg/L-water. These concentrations are similar to the Health Canada guideline concentration but they are 3-6 times the Japanese water quality standard.

Four percent formalin application for the management of radiation proctitis in carcinoma cervix patients: An effective, safe, and economical practice.

CONTEXT: Radiotherapy is a very effective treatment modality for pelvic malignancies such as carcinoma of the cervix. However, it is quite common for chronic radiation proctitis (CRP) to manifest after radical radiotherapy. CRP is a source of significant morbidity, and there is a lack of effective treatment modalities. There also exists a general lack of guidelines on management of CRP. AIMS: To assess the benefit from 4% formalin application for the treatment of Grade >2 CRP among patients previously treated with radical radiotherapy for cervical carcinoma. SETTINGS AND DESIGN: This retrospective descriptive study involved 29 eligible patients who were treated from November 2010 - November 2015 for CRP with 4% formalin application. MATERIALS AND METHODS: Of the 1864 patients of carcinoma cervix treated during the said patients, 29 patients fulfilled the eligibility criteria. Eligible patients were invited telephonically for follow-up and were assessed for response and complications of the procedure. RESULTS: The treatment of hemorrhagic radiation proctitis with local formalin instillation is effective, well tolerated and safe procedure. The procedure is inexpensive, technically simple and can be done on an outpatient basis. 62% patients had complete freedom from rectal bleed, while 34.5% patients had partial benefit. Only one patient required diversion colostomy for persistent bleeding.

Formaldehyde-releasers in cosmetics: relationship to formaldehyde contact allergy. Part 2. Patch test relationship to formaldehyde contact allergy, experimental provocation tests, amount of formaldehyde released, and assessment of risk to consumers allergic to formaldehyde.

This is the second part of an article on formaldehyde-releasers in cosmetics. The patch test relationship between the releasers in cosmetics to formaldehyde contact allergy is reviewed and it is assessed whether products preserved with formaldehyde-releasers may contain enough free formaldehyde to pose a threat to individuals with contact allergy to formaldehyde. There is a clear relationship between positive patch test reactions to formaldehyde-releasers and formaldehyde contact allergy: 15% of all reactions to 2-bromo-2-nitropropane-1,3-diol and 40-60% of the reactions to the other releasers are caused by a reaction to the formaldehyde in the test material. There is only fragmented data on the amount of free formaldehyde in cosmetics preserved with formaldehyde donors. However, all releasers (with the exception of 2-bromo-2-nitropropane-1,3-diol, for which adequate data are lacking) can, in the right circumstances of concentration and product composition, release >200 p.p.m. formaldehyde, which may result in allergic contact dermatitis. Whether this is actually the case in any particular product cannot be determined from the ingredient labelling. Therefore, we recommend advising patients allergic to formaldehyde to avoid leave-on cosmetics preserved with quaternium-15, diazolidinyl urea, DMDM hydantoin, or imidazolidinyl urea, acknowledging that many would tolerate some products.

Pharmacological assessment of the rat formalin test utilizing the clinically used analgesic drugs gabapentin, lamotrigine, morphine, duloxetine, tramadol and ibuprofen: influence of low and high formalin concentrations.

The formalin test is used as a primary behavioural screen for assaying the antinociceptive activity of compounds in laboratory rodents. After hindpaw formalin injection, nociceptive behaviours are expressed in a biphasic pattern and correlate closely with the concentration of formalin injected. Here, the antinociceptive efficacy of six compounds used in the clinical treatment of chronic pain was compared in rats injected with either 1% or 5% formalin. Predictably, the anti-inflammatory drug ibuprofen (30-300 mg/kg) attenuated second phase (16-40 min) nociceptive behaviours in 5% formalin-injected rats; 1% formalin-injected rats were unaffected. The anti-epileptic drugs gabapentin (50-200 mg/kg) and lamotrigine (10-60 mg/kg) were antinociceptive only during second phase in both 1% and 5% tests. Notably, they were 2-4 times more potent in 1% vs 5% formalin-injected rats. The dual monoamine reuptake inhibitor duloxetine (3-60 mg/kg) consistently attenuated nociceptive behaviours during first phase and interphase in both tests. However second phase nociception was only attenuated in 5% formalin-injected rats giving rise to a 6 fold increase in potency compared with 1% formalin-injected rats. The micro-opioid receptor agonist morphine (1-6 mg/kg) and the combined micro-opioid receptor agonist/monoamine reuptake inhibitor tramadol (5-50 mg/kg) both attenuated nociceptive behaviours throughout the duration of both the 1% and 5% tests; no difference in antinociceptive potency occurred for either compound during second phase. Thus, for mechanistically-distinct compounds the predictive antinociceptive capacity of the formalin test can vary with the concentration of formalin injected, likely as a result of peripheral and central nociceptive signalling mechanisms being differentially engaged.

Methods for assessing uncertainty in fundamental assumptions and associated models for cancer risk assessment.

The distributional approach for uncertainty analysis in cancer risk assessment is reviewed and extended. The method considers a combination of bioassay study results, targeted experiments, and expert judgment regarding biological mechanisms to predict a probability distribution for uncertain cancer risks. Probabilities are assigned to alternative model components, including the determination of human carcinogenicity, mode of action, the dosimetry measure for exposure, the mathematical form of the dose-response relationship, the experimental data set(s) used to fit the relationship, and the formula used for interspecies extrapolation. Alternative software platforms for implementing the method are considered, including Bayesian belief networks (BBNs) that facilitate assignment of prior probabilities, specification of relationships among model components, and identification of all output nodes on the probability tree. The method is demonstrated using the application of Evans, Sielken, and co-workers for predicting cancer risk from formaldehyde inhalation exposure. Uncertainty distributions are derived for maximum likelihood estimate (MLE) and 95th percentile upper confidence limit (UCL) unit cancer risk estimates, and the effects of resolving selected model uncertainties on these distributions are demonstrated, considering both perfect and partial information for these model components. A method for synthesizing the results of multiple mechanistic studies is introduced, considering the assessed sensitivities and selectivities of the studies for their targeted effects. A highly simplified example is presented illustrating assessment of genotoxicity based on studies of DNA damage response caused by naphthalene and its metabolites. The approach can provide a formal mechanism for synthesizing multiple sources of information using a transparent and replicable weight-of-evidence procedure.

Benchmark dose risk assessment for formaldehyde using airflow modeling and a single-compartment, DNA-protein cross-link dosimetry model to estimate human equivalent doses.

Formaldehyde induced squamous-cell carcinomas in the nasal passages of F344 rats in two inhalation bioassays at exposure levels of 6 ppm and above. Increases in rates of cell proliferation were measured by T. M. Monticello and colleagues at exposure levels of 0.7 ppm and above in the same tissues from which tumors arose. A risk assessment for formaldehyde was conducted at the CIIT Centers for Health Research, in collaboration with investigators from Toxicological Excellence in Risk Assessment (TERA) and the U.S. Environmental Protection Agency (U.S. EPA) in 1999. Two methods for dose-response assessment were used: a full biologically based modeling approach and a statistically oriented analysis by benchmark dose (BMD) method. This article presents the later approach, the purpose of which is to combine BMD and pharmacokinetic modeling to estimate human cancer risks from formaldehyde exposure. BMD analysis was used to identify points of departure (exposure levels) for low-dose extrapolation in rats for both tumor and the cell proliferation endpoints. The benchmark concentrations for induced cell proliferation were lower than for tumors. These concentrations were extrapolated to humans using two mechanistic models. One model used computational fluid dynamics (CFD) alone to determine rates of delivery of inhaled formaldehyde to the nasal lining. The second model combined the CFD method with a pharmacokinetic model to predict tissue dose with formaldehyde-induced DNA-protein cross-links (DPX) as a dose metric. Both extrapolation methods gave similar results, and the predicted cancer risk in humans at low exposure levels was found to be similar to that from a risk assessment conducted by the U.S. EPA in 1991. Use of the mechanistically based extrapolation models lends greater certainty to these risk estimates than previous approaches and also identifies the uncertainty in the measured dose-response relationship for cell proliferation at low exposure levels, the dose-response relationship for DPX in monkeys, and the choice between linear and nonlinear methods of extrapolation as key remaining sources of uncertainty.

Dosimetry modeling of inhaled formaldehyde: binning nasal flux predictions for quantitative risk assessment.

Interspecies extrapolations of tissue dose and tumor response have been a significant source of uncertainty in formaldehyde cancer risk assessment. The ability to account for species-specific variation of dose within the nasal passages would reduce this uncertainty. Three-dimensional, anatomically realistic, computational fluid dynamics (CFD) models of nasal airflow and formaldehyde gas transport in the F344 rat, rhesus monkey, and human were used to predict local patterns of wall mass flux (pmol/[mm(2)-h-ppm]). The nasal surface of each species was partitioned by flux into smaller regions (flux bins), each characterized by surface area and an average flux value. Rat and monkey flux bins were predicted for steady-state inspiratory airflow rates corresponding to the estimated minute volume for each species. Human flux bins were predicted for steady-state inspiratory airflow at 7.4, 15, 18, 25.8, 31.8, and 37 l/min and were extrapolated to 46 and 50 l/min. Flux values higher than half the maximum flux value (flux median) were predicted for nearly 20% of human nasal surfaces at 15 l/min, whereas only 5% of rat and less than 1% of monkey nasal surfaces were associated with fluxes higher than flux medians at 0.576 l/min and 4.8 l/min, respectively. Human nasal flux patterns shifted distally and uptake percentage decreased as inspiratory flow rate increased. Flux binning captures anatomical effects on flux and is thereby a basis for describing the effects of anatomy and airflow on local tissue disposition and distributions of tissue response. Formaldehyde risk models that incorporate flux binning derived from anatomically realistic CFD models will have significantly reduced uncertainty compared with risk estimates based on default methods.

Quantifying uncertainty in a risk assessment using human data.

A call for risk assessment approaches that better characterize and quantify uncertainty has been made by the scientific and regulatory community. This paper responds to that call by demonstrating a distributional approach that draws upon human data to derive potency estimates and to identify and quantify important sources of uncertainty. The approach is rooted in the science of decision analysis and employs an influence diagram, a decision tree, probabilistic weights, and a distribution of point estimates of carcinogenic potency. Its results estimate the likelihood of different carcinogenic risks (potencies) for a chemical under a specific scenario. For this exercise, human data on formaldehyde were employed to demonstrate the approach. Sensitivity analyses were performed to determine the relative impact of specific levels and alternatives on the potency distribution. The resulting potency estimates are compared with the results of an exercise using animal data on formaldehyde. The paper demonstrates that distributional risk assessment is readily adapted to situations in which epidemiologic data serve as the basis for potency estimates. Strengths and weaknesses of the distributional approach are discussed. Areas for further application and research are recommended.

Experimental assessment of the sensitizing properties of formaldehyde.

Formaldehyde causes upper respiratory tract irritation and has been reported in some investigations to be a cause of occupational allergic asthma. The data are equivocal, however, and it has proved difficult to confirm that exposure to formaldehyde induces respiratory sensitization or provokes the production of specific immunoglobulin E (IgE) antibody. In this study the sensitizing properties of formaldehyde were examined experimentally. This chemical elicited strong positive responses in three independent methods for the prospective identification of contact sensitizing chemicals-the guinea pig maximization test, the occluded patch test of Buehler and the murine local lymph node assay. In contrast, in a novel predictive test method for assessment of respiratory sensitization potential-the mouse IgE test-formaldehyde at the same test concentrations was negative. Furthermore, formaldehyde induced in mice a pattern of cytokine secretion by draining lymph node cells inconsistent with the stimulation of IgE antibody responses or respiratory sensitization. These data indicate that, although formaldehyde is a potent contact allergen, it lacks a significant potential to cause sensitization of the respiratory tract.

Measurement of skin-fold thickness in the guinea pig. Assessment of edema-inducing capacity of cutting fluids, acids, alkalis, formalin and dimethyl sulfoxide.

The rabbit has been used for decades for predictive testing of skin irritancy, but in recent years, the guinea pig has been suggested as an alternative, especially for assessment of one of the components of the irritant reaction: edema (fluid accumulation). A method based on skin-fold measurements with Harpenden calipers has been developed and modified. In previous papers, experience with sodium lauryl sulphate, nonanoic acid and industrial solvents was reported. The present results concern the use of cutting fluids, buffered and unbuffered acid and alkaline solutions, formalin and dimethyl sulfoxide. This inexpensive and comparatively unsophisticated method afforded clear dose-response relationships and good discriminating power. The only exception was the acid and alkaline solutions, where no changes in skin-fold thickness were observed despite their documented irritant potential. The appearance of erythema (visual scoring) and the increase in skin-fold thickness, and their relationship, are discussed with some illustrative examples. The method described is now well standardized and is suited for predictive testing of the edema-inducing capacity of chemicals and products.

[Repeated use of hemodialysis equipment in the same patient]. / Wielokrotne uzycie dializatorów do hemodializy u tego samego chorego.

The authors submit the development of research on multiple use of dialyzers and the present state of the capillary dialysers reuse procedure. At present automated reuse machines are used that utilise ++de-ionized rinsing water or reverse ultrafiltration with or without 0.5% solution of sodium hypochlorite, or 3% solution of hydrogen peroxide. Generally, the sterilisation employs 1-2% formaldehyde and Renalin (stabilised solution of peracetic and acetic acids and hydrogen peroxide); more seldom--5% solution of acetic acid and glutaraldehyde. The pre-rinsing procedure of dialysers could also be performed with these solutions, except formaldehyde. The authors present advantages and disadvantages of every rinsing and sterilising solutions, which are used at present. The protein coat on the dialyzer is removed effectively only with sodium hypochlorite. On the other hand, formaldehyde and Renalin are the most effective sterilising solutions. However, formaldehyde could provide the development of anti-N-like antibodies, and allergic-toxic reactions in some patients. Another problem is a negative effect of formaldehyde on the staff. Renalin's drawbacks are its photosensitivity, a corrosive character and high cost. Multiple use of reprocessed dialyzers in the same patient decreases the cost of haemodialysis by even 70%, not effecting the survival rate. Also it is of considerable medical advantage, i.e. decreases the rate of first use syndrome and improves biocompatibility at subsequent uses of the dialyzers. The decrease of elimination effectiveness is, generally, scarcely noticed, statistically irrelevant and of no essential clinical significance.

Selecting experimental data for use in quantitative risk assessment: an expert-judgement approach.

In many cancer risk assessments the experimental data used in statistical modeling are selected by applying generic guidelines. The guidelines exclude use of some types of experimental data and often appear arbitrary since rules rather than scientific judgments guide selection of data. This paper implements an alternative approach in which data are selected based on the judgments of practicing scientists. Eight such scientists were identified through an explicit selection procedure to help select data for use in a dose-response assessment of formaldehyde. Judgements about appropriate data sets were then elicited in personal interviews using a formal interview protocol. Appropriate data sets were fit to the multistage model and used as the basis for low-dose extrapolation. Low-dose risk estimates are shown to be sensitive to the selection of data, especially the treatment of benign tumors. The recommendations of the experts also differ in some respects from the choices made in previously published risk assessments. This suggests that scientific judgement may be an appropriate method to augment guidelines when a broad range of data is available. The paper argues that the expert judgment approach has some advantages that are worth considering.

Dose paradigms for inhaled vapors of primary carcinogens and their impact on risk assessment.

In the assessment of risk, several factors affect predictions: selection of reactive agent, selection of tumor incidence data, modeling of dose, scaling across species, adjustment for differences in duration and frequency of exposure, and selection of the most suitable risk extrapolation model. If the endpoints, exposure regimen, and the model for risk extrapolation are constant, then the review of dose paradigms will illustrate the effect of dose modeling on risk, since by definition the reactive agent is the primary carcinogen. The response incidence in lifetime inhalation bioassays of two primary carcinogens, ethylene oxide and formaldehyde, was used with different dose paradigms to estimate risk from maximum lifetime occupational exposures. The dose paradigms that will be considered include: concentration, concentration time product, retained dose, integrated blood concentration, and tissue exposure. The basis for across-species scaling and the assumptions underlying each dose paradigm were discussed.

Assessment of the systemic distribution and toxicity of formaldehyde following pulpotomy treatment: Part one.

This report, the first of a two-part study, was undertaken to quantitate the systemic distribution of formaldehyde from a pulpotomy site, and to compare this level to doses that elicit overt systemic pathology. Maxillary first molars of rats were pulpotomized and treated with 14C-labeled formaldehyde, for 5 minutes. Additionally, four groups of rats were infused with 10, 20, 30, or 50 percent of the first quantity applied to the site. The data show that approximately 30 percent of the 14C-formaldehyde placed in the pulp chamber was distributed systemically; 50 percent to 59 percent was expired as CO2; and 2 percent was excreted.