Ultrasensitive dose-response for asbestos cancer risk implied by new inflammation-mutation model.

Alterations in complex cellular phenotype each typically involve multistep activation of an ultrasensitive molecular switch (e.g., to adaptively initiate an apoptosis, inflammasome, Nrf2-ARE anti-oxidant, or heat-shock activation pathway) that triggers expression of a suite of target genes while efficiently limiting false-positive switching from a baseline state. Such switches exhibit nonlinear signal-activation relationships. In contrast, a linear no-threshold (LNT) dose-response relationship is expected for damage that accumulates in proportion to dose, as hypothesized for increased risk of cancer in relation to genotoxic dose according to the multistage somatic mutation/clonal-expansion theory of cancer, e.g., as represented in the Moolgavkar-Venzon-Knudsen (MVK) cancer model by a doubly stochastic nonhomogeneous Poisson process. Mesothelioma and lung cancer induced by exposure to carcinogenic (e.g., certain asbestos) fibers in humans and experimental animals are thought to involve modes of action driven by mutations, cytotoxicity-associated inflammation, or both, rendering ambiguous expectations concerning the nature of model-implied shape of the low-dose response for above-background increase in risk of incurring these endpoints. A recent Inflammation Somatic Mutation (ISM) theory of cancer posits instead that tissue-damage-associated inflammation that epigenetically recruits, activates and orchestrates stem cells to engage in tissue repair does not merely promote cancer, but rather is a requisite co-initiator (acting together with as few as two somatic mutations) of the most efficient pathway to any type of cancer in any reparable tissue (Dose-Response 2019; 17(2):1-12). This theory is reviewed, implications of this theory are discussed in relation to mesothelioma and lung cancer associated with chronic asbestos inhalation, one of the two types of ISM-required mutations is here hypothesized to block or impede inflammation resolution (e.g., by doing so for GPCR-mediated signal transduction by one or more endogenous autacoid specialized pro-resolving mediators or SPMs), and supporting evidence for this hypothesis is discussed.

Mechanisms and shapes of causal exposure-response functions for asbestos in mesotheliomas and lung cancers.

This paper summarizes recent insights into causal biological mechanisms underlying the carcinogenicity of asbestos. It addresses their implications for the shapes of exposure-response curves and considers recent epidemiologic trends in malignant mesotheliomas (MMs) and lung fiber burden studies. Since the commercial amphiboles crocidolite and amosite pose the highest risk of MMs and contain high levels of iron, endogenous and exogenous pathways of iron injury and repair are discussed. Some practical implications of recent developments are that: (1) Asbestos-cancer exposure-response relationships should be expected to have non-zero background rates; (2) Evidence from inflammation biology and other sources suggests that there are exposure concentration thresholds below which exposures do not increase inflammasome-mediated inflammation or resulting inflammation-mediated cancer risks above background risk rates; and (3) The size of the suggested exposure concentration threshold depends on both the detailed time patterns of exposure on a time scale of hours to days and also on the composition of asbestos fibers in terms of their physiochemical properties. These conclusions are supported by complementary strands of evidence including biomathematical modeling, cell biology and biochemistry of asbestos-cell interactions in vitro and in vivo, lung fiber burden analyses and epidemiology showing trends in human exposures and MM rates.

A toxicogenomic approach for the risk assessment of the food contaminant acetamide.

Acetamide (CAS 60-35-5) is detected in common foods. Chronic rodent bioassays led to its classification as a group 2B possible human carcinogen due to the induction of liver tumors in rats. We used a toxicogenomics approach in Wistar rats gavaged daily for 7 or 28 days at doses of 300 to 1500 mg/kg/day (mkd) to determine a point of departure (POD) and investigate its mode of action (MoA). Ki67 labeling was increased at doses ≥750 mkd up to 3.3-fold representing the most sensitive apical endpoint. Differential gene expression analysis by RNA-Seq identified 1110 and 1814 differentially expressed genes in male and female rats, respectively, following 28 days of treatment. Down-regulated genes were associated with lipid metabolism while up-regulated genes included cell signaling, immune response, and cell cycle functions. Benchmark dose (BMD) modeling of the Ki67 labeling index determined the BMD10 lower confidence limit (BMDL10) as 190 mkd. Transcriptional BMD modeling revealed excellent concordance between transcriptional POD and apical endpoints. Collectively, these results indicate that acetamide is most likely acting through a mitogenic MoA, though specific key initiating molecular events could not be elucidated. A POD value of 190 mkd determined for cell proliferation is suggested for risk assessment purposes.

Development of a novel method for estimating dermal contact with hand-applied cleaning solutions.

Quantitatively characterizing dermal exposure for workers and consumers performing tasks with hand-applied cleaning solution is complex as many of the assessment variables are scenario specific. One of the key variables necessary for quantitatively estimating dermal exposure is the surface area of the hand contacted by the cleaning solution. However, no relevant data or methods are available in the literature. This study evaluated the feasibility of a novel simulation approach to measure skin contact area specific to hand cleaning with various types of liquid cleaning products to refine exposure and risk estimates for users of these products. This approach incorporates cotton rags wetted with pigmented cleaning solutions, volunteers wearing white cotton gloves during hand cleaning with those cotton rags, and digital imaging of the pigmented solution-contacted gloves post-simulation to quantify area of the hand contacted by the cleaning solution. When applied across three separate cleaning solutions, a denatured alcohol, an aqueous solution, and a lacquer thinner, this novel method performed well in estimating both palmer and dorsal surface areas of the hand contacted during simulated cleaning. The volume of cleaning solution applied to the rag and thickness of the rag were consistent predictors of contacted surface area. For the denatured alcohol, the time spent cleaning was additionally correlated with contacted surface area. This study suggests that this novel simulation approach could be an important tool for reducing an important source of uncertainty in dermal exposure assessments involving hand-applied cleaning solutions.

Risks of Allergic Contact Dermatitis Elicited by Nickel, Chromium, and Organic Sensitizers: Quantitative Models Based on Clinical Patch Test Data.

Risks of allergic contact dermatitis (ACD) from consumer products intended for extended (nonpiercing) dermal contact are regulated by E.U. Directive EN 1811 that limits released Ni to a weekly equivalent dermal load of ≤0.5 µg/cm2 . Similar approaches for thousands of known organic sensitizers are hampered by inability to quantify respective ACD-elicitation risk levels. To help address this gap, normalized values of cumulative risk for eliciting a positive ("≥+") clinical patch test response reported in 12 studies for a total of n = 625 Ni-sensitized patients were modeled in relation to observed ACD-eliciting Ni loads, yielding an approximate lognormal (LN) distribution with a geometric mean and standard deviation of GMNi = 15 µg/cm2 and GSDNi = 8.0, respectively. Such data for five sensitizers (including formaldehyde and 2-hydroxyethyl methacrylate) were also ∼LN distributed, but with a common GSD value equal to GSDNi and with heterogeneous sensitizer-specific GM values each defining a respective ACD-eliciting potency GMNi /GM relative to Ni. Such potencies were also estimated for nine (meth)acrylates by applying this general LN ACD-elicitation risk model to respective sets of fewer data. ACD-elicitation risk patterns observed for Cr(VI) (n = 417) and Cr(III) (n = 78) were fit to mixed-LN models in which ∼30% and ∼40% of the most sensitive responders, respectively, were estimated to exhibit a LN response also governed by GSDNi . The observed common LN-response shape parameter GSDNi may reflect a common underlying ACD mechanism and suggests a common interim approach to quantitative ACD-elicitation risk assessment based on available clinical data.

Potential Exposure and Cancer Risk from Formaldehyde Emissions from Installed Chinese Manufactured Laminate Flooring.

Lumber Liquidators (LL) Chinese-manufactured laminate flooring (CLF) has been installed in >400,000 U.S. homes over the last decade. To characterize potential associated formaldehyde exposures and cancer risks, chamber emissions data were collected from 399 new LL CLF, and from LL CLF installed in 899 homes in which measured aggregate indoor formaldehyde concentrations exceeded 100 µg/m3 from a total of 17,867 homes screened. Data from both sources were combined to characterize LL CLF flooring-associated formaldehyde emissions from new boards and installed boards. New flooring had an average (±SD) emission rate of 61.3 ± 52.1 µg/m2 -hour; >one-year installed boards had ∼threefold lower emission rates. Estimated emission rates for the 899 homes and corresponding data from questionnaires were used as inputs to a single-compartment, steady-state mass-balance model to estimate corresponding residence-specific TWA formaldehyde concentrations and potential resident exposures. Only ∼0.7% of those homes had estimated acute formaldehyde concentrations >100 µg/m3 immediately after LL CLF installation. The TWA daily formaldehyde inhalation exposure within the 899 homes was estimated to be 17 µg/day using California Proposition 65 default methods to extrapolate cancer risk (below the regulation "no significant risk level" of 40 µg/day). Using a U.S. Environmental Protection Agency linear cancer risk model, 50th and 95th percentile values of expected lifetime cancer risk for residents of these homes were estimated to be 0.33 and 1.2 per 100,000 exposed, respectively. Based on more recent data and verified nonlinear cancer risk assessment models, LL CLF formaldehyde emissions pose virtually no cancer risk to affected consumers.

Linear-No-Threshold Default Assumptions are Unwarranted for Cytotoxic Endpoints Independently Triggered by Ultrasensitive Molecular Switches.

Crump's response in this issue to my critique of linear-no-threshold (LNT) default assumptions for noncancer and nongenotoxic cancer risks (Risk Analysis 2016; 36(3):589-604) is rebutted herein. Crump maintains that distinguishing between a low-dose linear dose response and a threshold dose response on the basis of dose-response data is impossible even for endpoints involving increased cytotoxicity. My rebuttal relies on descriptions and specific illustrations of two well-characterized ultrasensitive molecular switches that govern two key cytoprotective responses to cellular stress-heat shock response and antioxidant response element activation, respectively-each of which serve to suppress stress-induced apoptotic cell death unless overwhelmed. Because detailed dose-response data for each endpoint is shown to be J- or inverted-J-shaped with high confidence, and because independent pathways can explain background rates of apoptosis, LNT assumptions for this cytotoxic endpoint are unwarranted, at least in some cases and perhaps generally.

Malathion dermal permeability in relation to dermal load: Assessment by physiologically based pharmacokinetic modeling of in vivo human data.

Estimates of dermal permeability (Kp), obtained by fitting an updated human PBPK model for malathion to previously reported data on excreted urinary metabolites after 29 volunteers were dermally exposed to measured values of [14C]malathion dermal load (L), were used to examine the empirical relationship between Kp and L. The PBPK model was adapted from previously reported human biokinetic and PBPK models for malathion, fit to previously reported urinary excretion data after oral [14C]malathion intake by volunteers, and then augmented to incorporate a standard Kp approach to modeling dermal-uptake kinetics. Good to excellent PBPK-model fits were obtained to all of 29 sets of cumulative urinary metabolite-excretion data (ave. [±1 SD] R2 = 0.953 [±0.064]). Contrary to the assumption that Kp and L are independent typically applied for dermally administered liquids or solutions, the 29 PBPK-based estimates of Kp obtained for malathion exhibit a strong positive association with the 2/3rds power of L (log-log Pearson correlation = 0.925, p = ∼0). Possible explanations of this observation involving physico-chemical characteristics and/or in vivo cutaneous effects of malathion are discussed. The PBPK model presented, and our observation that Kp estimates obtained by fitting this model to human experimental urinary-excretion data correlate well with L2/3, allow more realistic assessments of absorbed and metabolized dose during or after a variety of scenarios involving actual or potential dermal or multi-route malathion exposures, including for pesticide workers or farmers who apply malathion to crops.

Linear-No-Threshold Default Assumptions for Noncancer and Nongenotoxic Cancer Risks: A Mathematical and Biological Critique.

To improve U.S. Environmental Protection Agency (EPA) dose-response (DR) assessments for noncarcinogens and for nonlinear mode of action (MOA) carcinogens, the 2009 NRC Science and Decisions Panel recommended that the adjustment-factor approach traditionally applied to these endpoints should be replaced by a new default assumption that both endpoints have linear-no-threshold (LNT) population-wide DR relationships. The panel claimed this new approach is warranted because population DR is LNT when any new dose adds to a background dose that explains background levels of risk, and/or when there is substantial interindividual heterogeneity in susceptibility in the exposed human population. Mathematically, however, the first claim is either false or effectively meaningless and the second claim is false. Any dose-and population-response relationship that is statistically consistent with an LNT relationship may instead be an additive mixture of just two quasi-threshold DR relationships, which jointly exhibit low-dose S-shaped, quasi-threshold nonlinearity just below the lower end of the observed "linear" dose range. In this case, LNT extrapolation would necessarily overestimate increased risk by increasingly large relative magnitudes at diminishing values of above-background dose. The fact that chemically-induced apoptotic cell death occurs by unambiguously nonlinear, quasi-threshold DR mechanisms is apparent from recent data concerning this quintessential toxicity endpoint. The 2009 NRC Science and Decisions Panel claims and recommendations that default LNT assumptions be applied to DR assessment for noncarcinogens and nonlinear MOA carcinogens are therefore not justified either mathematically or biologically.

Reassessment of MTBE cancer potency considering modes of action for MTBE and its metabolites.

A 1999 California state agency cancer potency (CP) evaluation of methyl tert-butyl ether (MTBE) assumed linear risk extrapolations from tumor data were plausible because of limited evidence that MTBE or its metabolites could damage DNA, and based such extrapolations on data from rat gavage and rat and mouse inhalation studies indicating elevated tumor rates in male rat kidney, male rat Leydig interstitial cells, and female rat leukemia/lymphomas. More recent data bearing on MTBE cancer potency include a rodent cancer bioassay of MTBE in drinking water; several new studies of MTBE genotoxicity; several similar evaluations of MTBE metabolites, formaldehyde, and tert-butyl alcohol or TBA; and updated evaluations of carcinogenic mode(s) of action (MOAs) of MTBE and MTBE metabolite's. The lymphoma/leukemia data used in the California assessment were recently declared unreliable by the U.S. Environmental Protection Agency (EPA). Updated characterizations of MTBE CP, and its uncertainty, are currently needed to address a variety of decision goals concerning historical and current MTBE contamination. To this end, an extensive review of data sets bearing on MTBE and metabolite genotoxicity, cytotoxicity, and tumorigenicity was applied to reassess MTBE CP and related uncertainty in view of MOA considerations. Adopting the traditional approach that cytotoxicity-driven cancer MOAs are inoperative at very low, non-cytotoxic dose levels, it was determined that MTBE most likely does not increase cancer risk unless chronic exposures induce target-tissue toxicity, including in sensitive individuals. However, the corresponding expected (or plausible upper bound) CP for MTBE conditional on a hypothetical linear (e.g., genotoxic) MOA was estimated to be ∼2 × 10(-5) (or 0.003) per mg MTBE per kg body weight per day for adults exposed chronically over a lifetime. Based on this conservative estimate of CP, if MTBE is carcinogenic to humans, it is among the weakest 10% of chemical carcinogens evaluated by EPA.

Unveiling variability and uncertainty for better science and decisions on cancer risks from environmental chemicals.

The National Research Council 2009 "Silver Book" panel report included a recommendation that the U.S. Environmental Protection Agency (EPA) should increase all of its chemical carcinogen (CC) potency estimates by ∼7-fold to adjust for a purported median-vs.-mean bias that I recently argued does not exist (Bogen KT. "Does EPA underestimate cancer risks by ignoring susceptibility differences?," Risk Analysis, 2014; 34(10):1780-1784). In this issue of the journal, my argument is critiqued for having flaws concerning: (1) intent, bias, and conservatism of EPA estimates of CC potency; (2) bias in potency estimates derived from epidemiology; and (3) human-animal CC-potency correlation. However, my argument remains valid, for the following reasons. (1) EPA's default approach to estimating CC risks has correctly focused on bounding average (not median) individual risk under a genotoxic mode-of-action (MOA) assumption, although pragmatically the approach leaves both inter-individual variability in CC-susceptibility, and widely varying CC-specific magnitudes of fundamental MOA uncertainty, unquantified. (2) CC risk estimates based on large epidemiology studies are not systematically biased downward due to limited sampling from broad, lognormal susceptibility distributions. (3) A good, quantitative correlation is exhibited between upper-bounds on CC-specific potency estimated from human vs. animal studies (n = 24, r = 0.88, p = 2 × 10(-8)). It is concluded that protective upper-bound estimates of individual CC risk that account for heterogeneity in susceptibility, as well as risk comparisons informed by best predictions of average-individual and population risk that address CC-specific MOA uncertainty, should each be used as separate, complimentary tools to improve regulatory decisions concerning low-level, environmental CC exposures.

Does EPA underestimate cancer risks by ignoring susceptibility differences?

A 2009 report of the National Research Council (NRC) recommended that the U.S. Environmental Protection Agency (EPA) increase its estimates of increased cancer risk from exposure to environmental agents by ∼7-fold, due to an approximate ∼25-fold typical ratio between the median and upper 95th percentile persons' cancer sensitivity assuming approximately lognormally distributed sensitivities. EPA inaction on this issue has raised concerns that cancer risks to environmentally exposed populations remain systematically underestimated. This concern is unwarranted, however, because EPA point estimates of cancer risk have always pertained to the average, not the median, person in each modeled exposure group. Nevertheless, EPA has yet to explain clearly how its risk characterization and risk management policies concerning individual risks from environmental chemical carcinogens do appropriately address broad variability in human cancer susceptibility that has been a focus of two major NRC reports to EPA concerning its risk assessment methods.

Dermal versus total uptake of benzene from mineral spirits solvent during parts washing.

Quantitative approaches to assessing exposure to, and associated risk from, benzene in mineral spirits solvent (MSS), used widely in parts washing and degreasing operations, have focused primarily on the respiratory pathway. The dermal contribution to total benzene uptake from such operations remains uncertain because measuring in vivo experimental dermal uptake of this volatile human carcinogen is difficult. Unprotected dermal uptake involves simultaneous sustained immersion events and transient splash/wipe events, each yielding residues subject to evaporation as well as dermal uptake. A two-process dermal exposure framework to assess dermal uptake to normal and damaged skin was applied to estimate potential daily dermal benzene dose (Dskin ) to workers who used historical or current formulations of recycled MSS in manual parts washers. Measures of evaporation and absorption of MSS dermally applied to human subjects were modeled to estimate in vivo dermal uptake of benzene in MSS. Uncertainty and interindividual variability in Dskin was characterized by Monte Carlo simulation, conditioned on uncertainty and/or variability estimated for each model input. Dermal exposures are estimated to average 33% of total (inhalation + dermal) benzene parts washing dose, with approximately equal predicted portions of dermal dose due to splash/wipe and to continuous contact with MSS. The estimated median (95th percentile) dermal and total daily benzene doses from parts washing are: 0.0069 (0.024) and 0.025 (0.18) mg/day using current, and 0.027 (0.085) and 0.098 (0.69) mg/day using historical, MSS solvents, respectively.

Dermal uptake of 18 dilute aqueous chemicals: in vivo disappearance-method measures greatly exceed in vitro-based predictions.

Average rates of total dermal uptake (Kup ) from short-term (e.g., bathing) contact with dilute aqueous organic chemicals (DAOCs) are typically estimated from steady-state in vitro diffusion-cell measures of chemical permeability (Kp ) through skin into receptor solution. Widely used ("PCR-vitro") methods estimate Kup by applying diffusion theory to increase Kp predictions made by a physico-chemical regression (PCR) model that was fit to a large set of Kp measures. Here, Kup predictions for 18 DAOCs made by three PCR-vitro models (EPA, NIOSH, and MH) were compared to previous in vivo measures obtained by methods unlikely to underestimate Kup . A new PCR model fit to all 18 measures is accurate to within approximately threefold (r = 0.91, p < 10(-5) ), but the PCR-vitro predictions (r > 0.63) all tend to underestimate the Kup measures by mean factors (UF, and p value for testing UF = 1) of 10 (EPA, p < 10(-6) ), 11 (NIOSH, p < 10(-8) ), and 6.2 (MH, p = 0.018). For all three PCR-vitro models, log(UF) correlates negatively with molecular weight (r(2) = 0.31 to 0.84, p = 0.017 to < 10(-6) ) but not with log(vapor pressure) as an additional predictor (p > 0.05), so vapor pressure appears not to explain the significant in vivo/PCR-vitro discrepancy. Until this discrepancy is explained, careful in vivo measures of Kup should be obtained for more chemicals, the expanded in vivo database should be compared to in vitro-based predictions, and in vivo data should be considered in assessing aqueous dermal exposure and its uncertainty.

More on the dynamics of dust generation: the effects of mixing and sanding chrysotile, calcium carbonate, and other components on the characteristics of joint-compound dusts.

An ongoing research effort designed to reconstruct the character of historical exposures associated with use of chrysotile-containing joint compounds naturally raised questions concerning how the character (e.g. particle size distributions) of dusts generated from use of recreated materials compares to dusts from similar materials manufactured historically. This also provided an opportunity to further explore the relative degree that the characteristics of dusts generated from a bulk material are mediated by the properties of the bulk material versus the mechanical processes applied to the bulk material by which the dust is generated. In the current study, the characteristics of dusts generated from a recreated ready mix and recreated dry mix were compared to each other, to dusts from a historical dry mix, and to dusts from the commercial chrysotile fiber (JM 7RF3) used in the recreated materials. The effect of sanding on the character of dusts generated from these materials was also explored. Dusts from the dry materials studied were generated and captured for analysis in a dust generator-elutriator. The recreated and historical joint compounds were also prepared, applied to drywall, and sanded inside sealed bags so that the particles produced from sanding could be introduced into the elutriator and captured for analysis. Comparisons of fiber size distributions in dusts from these materials suggest that dust from commercial fiber is different from dusts generated from the joint compounds, which are mixtures, and the differences persist whether the materials are sanded or not. Differences were also observed between sanded recreated ready mix and either the recreated dry mix or a historical dry mix, again whether sanded or not. In all cases, however, such differences disappeared when variances obtained from surrogate data were used to better represent the 'irreducible variation' of these materials. Even using the smaller study-specific variances, no differences were observed between the recreated dry mix and the historical dry mix, indicating that chrysotile-containing joint compounds can be recreated using historical formulations such that the characteristics of the modern material reasonably mimic those of a corresponding historical material. Similarly, no significant differences were observed between dusts from sanded and unsanded versions of similar materials, suggesting (as in previous studies) that the characteristics of asbestos-containing dusts are mediated primarily by the properties of the bulk material from which they are derived.

Generalized Haber's law for exponential concentration decline, with application to riparian-aquatic pesticide ecotoxicity.

A simple analytic solution to the dynamic version of Haber's law was derived, conditional on a specified toxic load exponent (n) and on exponential decline in environmental toxicant concentration. Such conditions are particularly relevant to assessing ecotoxicity risk posed (e.g., to juvenile salmonids) by agricultural organophosphate (OP) pesticides that are subject to degradation and/or dissipation. A dynamic Haber's law model was fit to previously published detailed data on lethality for two aquatic species induced by six agricultural OP pesticides, and more crude fits were obtained to less detailed data on five other OP and on two non-OP pesticides, indicating that for lethality, a range of 0.5 ≤ n ≤ 1.5 may be typical for OP pesticides. The AgDRIFT(®) stream deposition model was next used to establish that first-order or exponential loss, with dilution half-times on the order of ≤0.01 days, pertains approximately to pesticide residues in streams that arise after aerial application of agricultural pesticides 100 feet upwind. The analytic model was then applied to demonstrate that pesticide concentrations deposited in downwind streams following an aerial application are effectively diluted by about 50- to 300-fold from their initial concentration. Riparian ecotoxicity risk assessment models that ignore this effective dilution, and base pesticide-specific estimates of reduced survival on the initial concentrations, are therefore unrealistically conservative.

Measuring mixed cellulose ester (MCE) filter mass under variable humidity conditions.

Mixed cellulose ester (MCE) filters, used routinely to collect dust samples from air for fiber analysis, are the only filter type that can be prepared for both phased contrast microscopy and transmission electron microscopy analyses. However, whenever fiber counts require collecting dust masses <100 µg on a single filter under variable relative humidity (RH) conditions, historically noted effects of humidity on MCE filter mass can hinder accurate estimates of dust mass, measured as loaded minus unloaded filter mass (M). In this study, a baseline set of hundreds of paired measures of change in RH versus M over different time intervals were obtained over a 5-day period for replicate series of 40 unloaded 37-mm MCE filters under varying RH conditions at a nearly constant temperature. Similar baseline data were obtained for 25-mm MCE filters. Linear regressions fit to these data allow improved estimates of dust mass loaded onto MCE filters from measures of M and RH made before and after loading occurs. Using established theory, these relationships were generalized to address temperature variation as well, and examples of numerical applications are provided.

Chamber for testing asbestos-containing products: validation and testing of a re-created chrysotile-containing joint compound.

Joint compound products containing chrysotile asbestos were commonly used for building construction from the late 1940s through the mid-1970s. Few relevant data exist to support reconstructing historical worker exposures to fibers generated by working with this material. Therefore, we re-created 1960s-era chrysotile-containing joint compound (JCC) and compared its characteristics to a current-day asbestos-free joint compound (JCN). Validation studies showed that a bench-scale chamber with controlled flow dynamics, designed to quantify particulate emissions from joint compound products, provided precise and reliable measurements of generated airborne dust mass, chrysotile fiber concentrations, and corresponding activity-specific emission rates. Subsequent chamber studies characterized fibers counted by phase contrast microscopy (PCM) per mass of respirable dusts and total suspended particulate dusts (total dusts), generated during JCC sanding or sweeping, as well as corresponding dust emission rates for JCC and JCN, and the ratio of total to respirable dust mass for JCN. From these data we estimated factors, F(CH-rd) and F(CH-td) (in units of f cm(-3) per mg m(-3)), by which respirable JCN dust mass concentrations collected during construction use can be converted to corresponding airborne PCM fiber concentrations generated by sanding or sweeping JCC. For sanding, median values (95% confidence limits) of F(CH-rd) and F(CH-td) were estimated to be 0.044 (0.039-0.050) and 0.212 (0.115-0.390) f cm(-3) per mg m(-3), respectively. The F(CH-td) to F(CH-rd) ratio indicates that approximately five times as many airborne PCM fibers are anticipated per unit air volume sampled when JCC dust is collected on cassettes (as done historically), than when respirable JCC dust is collected on cyclones. As the sizes of individual fibers collected appear to be primarily respirable, this difference may be a sampling artifact and suggests caution in interpreting historical fiber concentration measures made using cassettes during work with JCC-like materials. F(CH-rd) can be used with published and newly generated field measurements of respirable dust mass concentrations associated with the use of JCN or equivalent JCN materials to better characterize historical worker exposures to PCM fibers from use of JCC or equivalent JCCs. The experimental process described also can be used to develop conversion factors for other combinations of modern-day asbestos-free and historical chrysotile-containing products.

Benzene inhalation by parts washers: new estimates based on measures of occupational exposure to solvent coaromatics.

Questions persist regarding assessment of workers' exposures to products containing low levels of benzene, such as mineral spirit solvent (MSS). This study summarizes previously unpublished data for parts-washing activities, and evaluates potential daily and lifetime cumulative benzene exposures incurred by workers who used historical and current formulations of a recycled mineral spirits solvent in manual parts washers. Measured benzene concentrations in historical samples from parts-washing operations were frequently below analytical detection limits. To better assess benzene exposure among these workers, air-to-solvent concentration ratios measured for toluene, ethylbenzene, and xylenes (TEX) were used to predict those for benzene based on a statistical model, conditional on physical-chemical theory supported by new thermodynamic calculations of TEX and benzene activity coefficients in a modeled MSS-type solvent. Using probabilistic methods, the distributions of benzene concentrations were then combined with distributions of other exposure parameters to estimate eight-hour time-weighted average (TWA) exposure concentration distributions and corresponding daily respiratory dose distributions for workers using these solvents in parts washers. The estimated 50th (95th) percentile of the daily respiratory dose and corresponding eight-hour TWA air concentration for workers performing parts washing are 0.079 (0.77) mg and 0.0030 (0.028) parts per million by volume (ppm) for historical solvent, and 0.020 (0.20) mg and 0.00078 (0.0075) ppm for current solvent, respectively. Both 95th percentile eight-hour TWA respiratory exposure estimates for solvent formulations are less than 10% of the current Occupational Safety and Health Administration permissible exposure limit of 1.0 ppm for benzene.