RESUMEN

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.

Asunto(s)

Amianto , Neoplasias Pulmonares , Mesotelioma , Humanos , Amianto/toxicidad , Mesotelioma/inducido químicamente , Mesotelioma/epidemiología , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/epidemiología , Pulmón/patología , Asbestos Anfíboles/toxicidad , Inflamación/metabolismo

RESUMEN

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.

Asunto(s)

Amianto , Carcinógenos Ambientales , Neoplasias Pulmonares , Mesotelioma , Animales , Humanos , Amianto/toxicidad , Mesotelioma/inducido químicamente , Mesotelioma/genética , Inflamación/inducido químicamente , Inflamación/metabolismo , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/genética , Carcinógenos Ambientales/toxicidad , Mutación

RESUMEN

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.

Asunto(s)

Detergentes , Monitoreo del Ambiente , Exposición Profesional , Absorción Cutánea , Mano , Humanos , Piel

RESUMEN

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.

Asunto(s)

Acetamidas/toxicidad , Carcinógenos/toxicidad , Contaminación de Alimentos , Neoplasias Hepáticas/genética , Modelos Biológicos , Animales , Carcinogénesis/inducido químicamente , Carcinogénesis/genética , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Proliferación Celular/efectos de los fármacos , Simulación por Computador , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inmunidad/efectos de los fármacos , Inmunidad/genética , Antígeno Ki-67/análisis , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/genética , Hígado/efectos de los fármacos , Hígado/patología , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/patología , Masculino , RNA-Seq , Ratas , Ratas Wistar , Medición de Riesgo/métodos , Pruebas de Toxicidad Crónica/métodos , Regulación hacia Arriba/efectos de los fármacos

RESUMEN

Linear-no-threshold (LNT) risk extrapolation has long been applied to estimate risks posed by low-level environmental carcinogen exposures, based on the 60-year-old multistage somatic mutation/clonal expansion (MSM) cancer theory. Recent evidence supports an alternative theory: Malignant tumors arise most efficiently from a stem cell that incurs requisite mutations and also is activated by inflammation to an epigenetically mediated and maintained state of adaptive hyperplasia (AH). This new inflammation-MSM (ISM) theory posits that inflammation-activated stem cells normally restricted to sites of injury-induced inflammation and tissue repair become uniquely susceptible to efficient carcinogenesis if normal post-inflammation AH termination is blocked by mutation. This theory posits that inflammation generally thus co-initiates cancer and transiently amplifies activated stem cells, implying that MSM theory (eg, the 2-stage stochastic "Moolgavkar, Venzon, Knudson [MVK]" model) is incomplete. Because inflammation dose-response typically is not LNT, the ISM theory predicts this is also true for most (perhaps all) carcinogens. The ISM (but not the MVK) model is shown to be consistent with recent data showing ∼100% carcinoma incidence (but not DNA adducts) in livers of rats exposed to aflatoxin B1 and was eliminated when that dose was co-administered with a highly potent anti-inflammatory agent. Experimental approaches to test ISM theory more robustly are discussed.

RESUMEN

The 2016 U.S. Environmental Protection Agency (EPA) Integrated Risk Information System (IRIS) assessment for ethylene oxide (EO) estimated a 10-6 increased inhalation cancer risk of 0.1 parts per trillion, based on National Institute of Occupational Safety and Health (NIOSH) epidemiology studies of sterilization facility workers exposed to EO between 1938 and 1986. The worker exposure estimates were based on a NIOSH statistical regression (NSR) model "validated" with EO levels measured after 1978. Between 1938 and 1978, when EO data was unavailable, the NSR model predicts exposures lowest in 1938 increasing to peak levels in 1978. That increasing EO concentration trend arose, in part, because engineering/industrial-hygiene (E/IH) factors associated with evolving EO-sterilization equipment and operations before 1978 were not properly considered in the NSR model. To test the NSR model trend prediction, a new E/IH-based model was developed using historical data on EO kill concentrations, EO residue levels in sterilized materials, post-wash EO concentrations in a sterilization chamber, and information on facility characteristics and sterilizer operator practices from operators familiar with pre-1978 industry conditions. The E/IH 90th percentile of 8 h time-weighted average EO exposures (C90) for highly exposed sterilizer operators was calibrated to match 1978 C90 values from the NSR model. E/IH model C90 exposures were estimated to decrease over time from levels 16 and were four-fold greater than NSR-estimated exposures for workers during 1938-1954 and 1955-1964. This E/IH modeled trend is opposite to that of NSR model predictions of exposures before 1978, suggesting that EPA's exclusive reliance on the NIOSH cohort to estimate EO cancer risk should be re-examined.

Asunto(s)

Desinfectantes/análisis , Óxido de Etileno/análisis , Exposición Profesional/análisis , Esterilización , Estudios de Cohortes , Desinfectantes/historia , Óxido de Etileno/historia , Historia del Siglo XX , Humanos , National Institute for Occupational Safety and Health, U.S. , Exposición Profesional/historia , Salud Laboral , Medición de Riesgo , Estados Unidos , United States Environmental Protection Agency

RESUMEN

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.

Asunto(s)

Materiales de Construcción , Formaldehído/análisis , Neoplasias/inducido químicamente , Medición de Riesgo , Contaminantes Atmosféricos/análisis , Contaminación del Aire Interior/análisis , Algoritmos , California , China , Formaldehído/efectos adversos , Humanos , Exposición por Inhalación/análisis , Modelos Lineales , Neoplasias/prevención & control , Hipersensibilidad Respiratoria/prevención & control , Estados Unidos , United States Environmental Protection Agency

RESUMEN

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.

RESUMEN

The in vitro arsenite (AsIII) cytotoxicity dose-response (DR) of human keratinocytes (HEK001) was examined at greater statistical resolution than ever previously reported using the MTT assay to determine cell viability. Fifty-four 96-well plates were treated with AsIII concentrations of 0.25, 0.5, 1, 2, 3, 4, 5, 7, 10, 15, 20, 25, or 30 µM. Because of unexpected variation in viability response patterns, a two-stage DR analysis was used in which data on plate-specific viability (%), estimated as 100% times the ratio of measured viability in exposed to unexposed cells, were fit initially to a generalized lognormal response function positing that HEK001 cells studied consisted of: a proportion P of relatively highly sensitive (HS) cells, a proportion Po of relatively resistant cells, and a remaining (1-P-Po) fraction of typical-sensitivity (TS) cells exhibiting the intermediate level of AsIII sensitivity characteristic of most cells in each assay. The estimated fractions P and Po were used to adjust data from all 54 plates (and from the 28 plates yielding the best fits) to reflect the condition that P = Po = 0 to provide detailed DR analysis specifically for TS cells. Four DR models fit to the combined adjusted data were each very predictive (R2 > 0.97) overall but were inconsistent with at least one of the data set examined (p < 10-5). Adjusted mean responses at ≤3 µM were approximately equal (p > 0.30) and exceeded 100% significance (p ≤ 10-6). A low-dose hormetic model provided the best fit to the combined adjusted data for TS cells (R2 = 0.995). Marked variability in estimates of P (the proportion of apparent HS cells) was unexpected, not readily explained, and warrants further study using additional cell lines and assay methods, and in vivo.

RESUMEN

Kelch-like ECH-associated protein 1 (Keap1), nuclear factor erythroid 2-like factor 2-related factor 2 (Nrf2), and the antioxidant response element (ARE) are interacting components of a master regulatory signaling pathway that coordinates redox homeostasis, cytoprotective responses, and shifts in stem cell state. This study reexamined detailed dose-response (DR) data reported for in vitro Nrf2-ARE activation in human hepatoblastoma HepG2 cell lines containing either a ARE-bla or ARE-luc reporter at 12 different concentrations of each of 15 chemicals. The normalized study data were combined among chemicals exhibiting a positive response, yielding n = 531 (179) DR data for 9 (7) chemicals using the ARE-bla (ARE-luc) assay. Three-parameter linear/kth-power regression fits obtained to each combined set of ARE-bla- or ARE-luc-assay response data provided good fits (R2 = .99 or .91, respectively, Pfit > .99) that each incorporate a highly significant negative initial linear slope (P = 4 × 10-5 or .00025) and an overall J-shaped DR pattern. Results from this reanalysis of high-resolution ARE response data support the hypothesis that nonlinear ARE-mediated adaptive cellular responses to oxidative stress are governed by an ultrasensitive molecular switch.

RESUMEN

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.

RESUMEN

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.

Asunto(s)

Malatión/farmacocinética , Modelos Biológicos , Radioisótopos de Carbono/farmacocinética , Radioisótopos de Carbono/orina , Femenino , Humanos , Cinética , Malatión/administración & dosificación , Masculino , Permeabilidad , Plaguicidas/farmacocinética , Absorción Cutánea

RESUMEN

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.

Asunto(s)

Carcinógenos/toxicidad , Neoplasias/inducido químicamente , Medición de Riesgo/métodos , Apoptosis , Carcinogénesis , Línea Celular , Relación Dosis-Respuesta a Droga , Exposición a Riesgos Ambientales , Humanos , Modelos Teóricos , Distribución Normal , Factores de Riesgo , Estados Unidos , United States Environmental Protection Agency

RESUMEN

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.

Asunto(s)

Carcinógenos Ambientales/toxicidad , Éteres Metílicos/toxicidad , Contaminantes Atmosféricos/toxicidad , Animales , Biotransformación , Formaldehído/toxicidad , Humanos , Mutágenos/toxicidad , Medición de Riesgo , Toxicocinética , Estados Unidos , United States Environmental Protection Agency , Contaminantes del Agua/toxicidad , Alcohol terc-Butílico/toxicidad

RESUMEN

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.

Asunto(s)

Carcinógenos/toxicidad , Exposición a Riesgos Ambientales , Neoplasias/epidemiología , Incertidumbre , Humanos , Neoplasias/inducido químicamente , Medición de Riesgo , Factores de Riesgo , Estados Unidos , United States Environmental Protection Agency

RESUMEN

ED001-study data on increased liver and stomach tumor risks in >40,000 trout fed dibenzo[a,l]pyrene (DBP), one of the most potently mutagenic chemical carcinogens known, provide the greatest low-dose dose-response resolution of any experimentally induced tumor data set to date. Although multistage somatic mutation/clonal-expansion cancer theory predicts that genotoxic carcinogens increase tumor risk in linear no-threshold proportion to dose at low doses, ED001 tumor data curiously exhibit substantial low-dose nonlinearity. To explore the role that nongenotoxic mechanisms may have played to yield such nonlinearity, the liver and stomach tumor data sets were each fit by two models that each assume a genotoxic and a nongenotoxic pathway to increased tumor risk: the stochastic 2-stage (MVK) cancer model, and a model implementing the more recent dysregulated adaptive hyperplasia (DAH) theory of tumorigenesis. MVK and DAH fits to the data sets were each excellent, but unexpectedly each MVK fit implies that DBP acts to increase tumor risk by entirely non-mutagenic mechanisms. Given that DBP is such a potent mutagen, the MVK-model fits obtained appear to be biologically implausible, whereas the DAH-model fits reflect that model's assumption that chemical-induced tumorigenesis typically is driven by elevated repair-cell populations rather than mutations per se.

RESUMEN

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.

Asunto(s)

Benceno/metabolismo , Piel/metabolismo , Solventes/química , Benceno/química , Humanos

RESUMEN

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.

Asunto(s)

Neoplasias/epidemiología , Susceptibilidad a Enfermedades , Humanos , Factores de Riesgo , Estados Unidos/epidemiología , United States Environmental Protection Agency

Asunto(s)

Conflicto de Intereses , Revisión de la Investigación por Pares/normas , Publicaciones Periódicas como Asunto/normas , Humanos

RESUMEN

Seven current contending cancer theories consider different sets of critical events as sufficient for tumorigenesis. These theories, most recently the microRNA dysregulation (MRD) theory, have overlapping attributes and extensive empirical support, but also some discrepancies, and some do not address both benign and malignant tumorigenesis. By definition, the most efficient tumorigenic pathways will dominate under conditions that selectively activate those pathways. The MRD theory provides a mechanistic basis to combine elements of the current theories into a new hypothesis that: (i) tumors arise most efficiently under stress that induces and sustains either protective or regenerative states of adaptive hyperplasia (AH) that normally are epigenetically maintained unless terminated; and (ii) if dysregulated by a somatic mutation that prevents normal termination, these two AH states can generate benign and malignant tumors, respectively. This hypothesis, but not multistage cancer theory, predicts that key participating AH-stem-cell populations expand markedly when triggered by stress, particularly chronic metabolic or oxidative stress, mechanical irritation, toxic exposure, wounding, inflammation, and/or infection. This hypothesis predicts that microRNA expression patterns in benign vs. malignant tumor tissue will correlate best with those governing protective vs. regenerative AH in that tissue, and that tumors arise most efficiently inmutagen-exposed stem cells that either happen to be in, or incidentally later become recruited into, an AH state.

Asunto(s)

Transformación Celular Neoplásica , Hiperplasia/fisiopatología , MicroARNs/metabolismo , Modelos Biológicos , Estrés Fisiológico/fisiología , Epigénesis Genética/fisiología , Perfilación de la Expresión Génica/métodos , Humanos , Hiperplasia/genética , MicroARNs/genética , Mutación/genética , Miocitos del Músculo Liso/metabolismo , Estrés Fisiológico/genética