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1.
Chem Res Toxicol ; 35(1): 7-29, 2022 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-34910474

RESUMEN

Cancer remains the second most frequent cause of death in human populations worldwide, which has been reflected in the emphasis placed on management of risk from environmental chemicals considered to be potential human carcinogens. The formation of DNA adducts has been considered as one of the key events of cancer, and persistence and/or failure of repair of these adducts may lead to mutation, thus initiating cancer. Some chemical carcinogens can produce DNA adducts, and DNA adducts have been used as biomarkers of exposure. However, DNA adducts of various types are also produced endogenously in the course of normal metabolism. Since both endogenous physiological processes and exogenous exposure to xenobiotics can cause DNA adducts, the differentiation of the sources of DNA adducts can be highly informative for cancer risk assessment. This review summarizes a highly applicable methodology, termed stable isotope labeling and mass spectrometry (SILMS), that is superior to previous methods, as it not only provides absolute quantitation of DNA adducts but also differentiates the exogenous and endogenous origins of DNA adducts. SILMS uses stable isotope-labeled substances for exposure, followed by DNA adduct measurement with highly sensitive mass spectrometry. Herein, the utilities and advantage of SILMS have been demonstrated by the rich data sets generated over the last two decades in improving the risk assessment of chemicals with DNA adducts being induced by both endogenous and exogenous sources, such as formaldehyde, vinyl acetate, vinyl chloride, and ethylene oxide.


Asunto(s)
Carcinógenos/análisis , Aductos de ADN/análisis , Animales , Humanos , Marcaje Isotópico , Espectrometría de Masas
2.
Regul Toxicol Pharmacol ; 77: 167-74, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26851508

RESUMEN

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.


Asunto(s)
Pruebas de Carcinogenicidad/métodos , Fijadores/toxicidad , Formaldehído/toxicidad , Leucemia/inducido químicamente , Neoplasias Nasofaríngeas/inducido químicamente , Animales , Carcinoma , Aductos de ADN/genética , Aductos de ADN/metabolismo , Relación Dosis-Respuesta a Droga , Fijadores/farmacocinética , Formaldehído/farmacocinética , Haplorrinos , Humanos , Exposición por Inhalación/efectos adversos , Leucemia/genética , Leucemia/metabolismo , Leucemia/mortalidad , Modelos Estadísticos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/mortalidad , Ratas , Medición de Riesgo , Especificidad de la Especie , Incertidumbre
3.
Toxicol Sci ; 146(1): 170-82, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25904104

RESUMEN

Formaldehyde is not only a widely used chemical with well-known carcinogenicity but is also a normal metabolite of living cells. It thus poses unique challenges for understanding risks associated with exposure. N(2-)hydroxymethyl-dG (N(2)-HOMe-dG) is the main formaldehyde-induced DNA mono-adduct, which together with DNA-protein crosslinks (DPCs) and toxicity-induced cell proliferation, play important roles in a mutagenic mode of action for cancer. In this study, N(2)-HOMe-dG was shown to be an excellent biomarker for direct adduction of formaldehyde to DNA and the hydrolysis of DPCs. The use of inhaled [(13)CD2]-formaldehyde exposures of rats and primates coupled with ultrasensitive nano ultra performance liquid chromatography-tandem mass spectrometry permitted accurate determinations of endogenous and exogenous formaldehyde DNA damage. The results show that inhaled formaldehyde only reached rat and monkey noses, but not tissues distant to the site of initial contact. The amounts of exogenous adducts were remarkably lower than those of endogenous adducts in exposed nasal epithelium. Moreover, exogenous adducts accumulated in rat nasal epithelium over the 28-days exposure to reach steady-state concentrations, followed by elimination with a half-life (t1/2) of 7.1 days. Additionally, we examined artifact formation during DNA preparation to ensure the accuracy of nonlabeled N(2)-HOMe-dG measurements. These novel findings provide critical new data for understanding major issues identified by the National Research Council Review of the 2010 Environmental Protection Agency's Draft Integrated Risk Information System Formaldehyde Risk Assessment. They support a data-driven need for reflection on whether risks have been overestimated for inhaled formaldehyde, whereas underappreciating endogenous formaldehyde as the primary source of exposure that results in bone marrow toxicity and leukemia in susceptible humans and rodents deficient in DNA repair.


Asunto(s)
Daño del ADN , ADN/efectos de los fármacos , Formaldehído/toxicidad , Animales , Cromatografía Líquida de Alta Presión , Humanos , Hidrólisis , Ratas , Espectrometría de Masas en Tándem
5.
Crit Rev Toxicol ; 44 Suppl 1: 1-81, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24793953

RESUMEN

Perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS) are ubiquitous synthetic chemicals with no known effect on human cancer development. This article systematically and critically reviews the epidemiologic evidence regarding the association between PFOA and PFOS exposure and cancer risk in humans. Eighteen epidemiologic studies - eight of PFOA, four of PFOS, and six of both PFOA and PFOS - have estimated associations of exposure to these chemicals with cancer incidence or mortality, with studies equally divided between occupational and nonoccupational settings. Although some statistically significant positive associations have been reported, for example, with cancers of the prostate, kidney, testis, and thyroid, the majority of relative risk estimates for both PFOA and PFOS have been between 0.5 and 2.0 (with 95% confidence intervals including 1.0), inconsistently detected across studies, counterbalanced by negative associations, not indicative of a monotonic exposure-response relationship, and not coherent with toxicological evidence in animals, in which the primary target organs are the liver, testis (Leydig cells), and pancreas (acinar cells). Many positive associations with PFOA exposure were detected in community settings without occupational exposure and were not supported by results in exposed workers. Given that occupational exposure to PFOA and PFOS is one to two orders of magnitude higher than environmental exposure, the discrepant positive findings are likely due to chance, confounding, and/or bias. Taken together, the epidemiologic evidence does not support the hypothesis of a causal association between PFOA or PFOS exposure and cancer in humans.


Asunto(s)
Ácidos Alcanesulfónicos/toxicidad , Caprilatos/toxicidad , Fluorocarburos/toxicidad , Neoplasias/epidemiología , Animales , Exposición a Riesgos Ambientales/efectos adversos , Humanos , Neoplasias/etiología , Neoplasias/patología , Exposición Profesional/efectos adversos , Riesgo
6.
Regul Toxicol Pharmacol ; 69(3): 333-7, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24793260

RESUMEN

The US Environmental Protection Agency (USEPA) is currently conducting a toxicological review of vanadium pentoxide (V2O5). As part of that effort, the Agency will need to address the fact that while a National Toxicology Program (NTP) chronic inhalation bioassay of V2O5 produced clear evidence of treatment-related lung tumors in both male and female B6C3F1 mice, neither of these responses were dose-related across the groups exposed to 1, 2, and 4mg/m(3). While lung tumor incidence was significantly elevated in all three exposed groups relative to that in the control groups, it was essentially flat across them. Herein we report results from computing poly-3-adjusted Cochran-Armitage trend test statistics with and without inclusion of the lung tumor incidence data from control group mice. These results confirm the absence of any significant dose-related effect on mouse lung tumor incidence in the study groups exposed to V2O5. We also considered two estimates of area under the vanadium lung burden versus time curve as plausible alternative dose metrics to the V2O5 chamber concentration. However, these alternative dose metrics were so highly correlated with the V2O5 chamber concentration (r=0.998) that nothing is to be gained from their use in place of the V2O5 chamber concentration in attempts to perform dose-response modeling of the tumor incidence or unit cancer risk computations. At the present time, there is no scientific basis to support linear (or nonlinear) extrapolations of estimated cancer risks to V2O5 exposure levels below 1mg/m(3). Additional tumor data at multiple V2O5 concentrations lower than 1mg/m(3) are required to support such extrapolations.


Asunto(s)
Carcinogénesis/inducido químicamente , Carcinógenos/toxicidad , Exposición por Inhalación/efectos adversos , Compuestos de Vanadio/efectos adversos , Animales , Bioensayo/métodos , Femenino , Incidencia , Pulmón/efectos de los fármacos , Neoplasias Pulmonares/inducido químicamente , Masculino , Ratones , Ratas , Medición de Riesgo , Estados Unidos
7.
Regul Toxicol Pharmacol ; 65(3): 311-5, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23352840

RESUMEN

We propose a novel bottom-up approach to the bounding of low-dose human cancer risks from chemical exposures that does not rely at all upon high-dose data for human or animal cancers. This approach can thus be used to provide an independent "reality check" on low-dose risk estimates derived with dose-response models that are fit to high-dose cancer data. The approach (1) is consistent with the "additivity to background" concept, (2) yields central and upper-bound risk estimates that are linear at all doses, and (3) requires only information regarding background risk, background (endogenous) exposure, and the additional exogenous exposure of interest in order to be implemented. After describing the details of this bottom-up approach, we illustrate its application using formaldehyde as an example. Results indicate that recent top-down risk extrapolations from occupational cohort mortality data for workers exposed to formaldehyde are overly conservative by substantial margins.


Asunto(s)
Carcinógenos/toxicidad , Desinfectantes/toxicidad , Formaldehído/toxicidad , Exposición Profesional/efectos adversos , Relación Dosis-Respuesta a Droga , Humanos , Medición de Riesgo
8.
Toxicol Pathol ; 41(2): 181-9, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23160431

RESUMEN

Formaldehyde is a widely used high production chemical that is also released as a byproduct of combustion, off-gassing of various building products, and as a fixative for pathologists and embalmers. What is not often realized is that formaldehyde is also produced as a normal physiologic chemical in all living cells. In 1980, chronic inhalation of high concentrations of formaldehyde was shown to be carcinogenic, inducing a high incidence of nasal squamous cell carcinomas in rats. Some epidemiologic studies have also found increased numbers of nasopharyngeal carcinoma and leukemia in humans exposed to formaldehyde that resulted in formaldehyde being considered a Known Human Carcinogen. This article reviews the data for rodent and human carcinogenicity, early Mode of Action studies, more recent molecular studies of both endogenous and exogenous DNA adducts, and epigenetic studies. It goes on to demonstrate the power of these research studies to provide critical data to improve our ability to develop science-based cancer risk assessments, instead of default approaches. The complexity of constant physiologic exposure to a known carcinogen requires that new ways of thinking be incorporated into determinations of cancer risk assessment for formaldehyde, other endogenous carcinogens, and the role of background endogenous DNA damage and mutagenesis.


Asunto(s)
Formaldehído/toxicidad , Neoplasias/inducido químicamente , Animales , Pruebas de Carcinogenicidad , Ecotoxicología , Formaldehído/envenenamiento , Humanos , Medición de Riesgo
9.
Regul Toxicol Pharmacol ; 64(1): 155-60, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22749912

RESUMEN

The National Toxicology Program (NTP) chronic inhalation bioassay of vanadium pentoxide (V(2)O(5)) produced "clear" evidence of lung tumors in B6C3F1 mice, but only "some" and "equivocal" evidence in male and female F344/N rats, respectively. No significant pairwise differences or trends with V(2)O(5) concentration in male or female rat poly-3-adjusted tumor incidence were reported. The "some" and "equivocal" evidence descriptors arose from comparisons of V(2)O(5)-exposed group incidence rates with NTP-2000- and NIH-07-fed historical control (HC) group incidence ranges. NTP acknowledged that use of data from NIH-07-fed HC groups could be inappropriate because the V(2)O(5) study used the NTP-2000 diet, but few studies using this newer diet were available then. We supplemented the early NTP-2000 diet HC data with data from 25 additional NTP-2000 diet studies conducted subsequent to the V(2)O(5) bioassay. This widened the HC tumor incidence ranges, thereby weakening the limited evidence for the carcinogenicity of inhaled V(2)O(5) in rats relative to HCs. The male rat control group in the V(2)O(5) study also appeared to be a near-"outlier" relative to the expanded HC database, potentially invalidating any comparisons of exposed group incidence rates with those for HCs. We conclude that there is "no" evidence of V(2)O(5) carcinogenicity in male or female F344/N rats.


Asunto(s)
Adenocarcinoma/etiología , Adenoma/etiología , Carcinógenos/toxicidad , Interpretación Estadística de Datos , Neoplasias Pulmonares/etiología , Compuestos de Vanadio/toxicidad , Adenocarcinoma/epidemiología , Adenocarcinoma/patología , Adenoma/epidemiología , Adenoma/patología , Administración por Inhalación , Animales , Pruebas de Carcinogenicidad , Carcinógenos/clasificación , Relación Dosis-Respuesta a Droga , Femenino , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratas , Ratas Endogámicas F344 , Especificidad de la Especie , Factores de Tiempo , Estados Unidos/epidemiología , Compuestos de Vanadio/clasificación
10.
Toxicol Sci ; 120 Suppl 1: S130-45, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21163908

RESUMEN

There is a strong need for science-based risk assessment that utilizes known data from diverse sources to arrive at accurate assessments of human health risk. Such assessments will protect the public health without mandating unreasonable regulation. This paper utilizes 30 years of research on three "known human carcinogens": formaldehyde, vinyl chloride (VC), and ethylene oxide (EO), each of which forms DNA adducts identical to endogenous DNA adducts in all individuals. It outlines quantitative data on endogenous adducts, mutagenicity, and relationships between endogenous and exogenous adducts. Formaldehyde has the richest data set, with quantitative data on endogenous and exogenous DNA adducts from the same samples. The review elaborates on how such data can be used to inform the current risk assessment on formaldehyde, including both the biological plausibility and accuracy of projected risks. Finally, it extends the thought process to VC, EO, and additional areas of potential research, pointing out needs, nuances, and potential paths forward to improved understanding that will lead to strong science-based risk assessment.


Asunto(s)
Carcinógenos/toxicidad , Aductos de ADN/toxicidad , ADN/efectos de los fármacos , Epidemiología Molecular/métodos , Neoplasias/inducido químicamente , Animales , Carcinógenos/química , Aductos de ADN/química , Óxido de Etileno/toxicidad , Formaldehído/toxicidad , Humanos , Neoplasias/epidemiología , Neoplasias/genética , Medición de Riesgo , Cloruro de Vinilo/toxicidad
11.
J Toxicol Environ Health B Crit Rev ; 13(7-8): 546-78, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21170809

RESUMEN

There is a need to define exposure-response curves for both Cu excess and deficiency to assist in determining the acceptable range of oral intake. A comprehensive database has been developed where different health outcomes from elevated and deficient Cu intakes were assigned ordinal severity scores to create common measures of response. A generalized linear model for ordinal data was used to estimate the probability of response associated with dose, duration and severity. The model can account for differences in animal species, the exposure medium (drinking water and feed), age, sex, and solubility. Using this model, an optimal intake level of 2.6 mg Cu/d was determined. This value is higher than the current U.S. recommended dietary intake (RDI; 0.9 mg/d) that protects against toxicity from Cu deficiency. It is also lower than the current tolerable upper intake level (UL; 10 mg/d) that protects against toxicity from Cu excess. Compared to traditional risk assessment approaches, categorical regression can provide risk managers with more information, including a range of intake levels associated with different levels of severity and probability of response. To weigh the relative harms of deficiency and excess, it is important that the results be interpreted along with the available information on the nature of the responses that were assigned to each severity score.


Asunto(s)
Cobre/deficiencia , Cobre/toxicidad , Adulto , Factores de Edad , Animales , Relación Dosis-Respuesta a Droga , Exposición a Riesgos Ambientales , Femenino , Humanos , Masculino , Ratones , Política Nutricional , Ratas , Valores de Referencia , Factores Sexuales , Especificidad de la Especie
12.
Regul Toxicol Pharmacol ; 49(3): 285-300, 2007 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-17949874

RESUMEN

A revised assessment of dichloromethane (DCM) has recently been reported that examines the influence of human genetic polymorphisms on cancer risks using deterministic PBPK and dose-response modeling in the mouse combined with probabilistic PBPK modeling in humans. This assessment utilized Bayesian techniques to optimize kinetic variables in mice and humans with mean values from posterior distributions used in the deterministic modeling in the mouse. To supplement this research, a case study was undertaken to examine the potential impact of probabilistic rather than deterministic PBPK and dose-response modeling in mice on subsequent unit risk factor (URF) determinations. Four separate PBPK cases were examined based on the exposure regimen of the NTP DCM bioassay. These were (a) Same Mouse (single draw of all PBPK inputs for both treatment groups); (b) Correlated BW-Same Inputs (single draw of all PBPK inputs for both treatment groups except for bodyweights (BWs), which were entered as correlated variables); (c) Correlated BW-Different Inputs (separate draws of all PBPK inputs for both treatment groups except that BWs were entered as correlated variables); and (d) Different Mouse (separate draws of all PBPK inputs for both treatment groups). Monte Carlo PBPK inputs reflect posterior distributions from Bayesian calibration in the mouse that had been previously reported. A minimum of 12,500 PBPK iterations were undertaken, in which dose metrics, i.e., mg DCM metabolized by the GST pathway/L tissue/day for lung and liver were determined. For dose-response modeling, these metrics were combined with NTP tumor incidence data that were randomly selected from binomial distributions. Resultant potency factors (0.1/ED(10)) were coupled with probabilistic PBPK modeling in humans that incorporated genetic polymorphisms to derive URFs. Results show that there was relatively little difference, i.e., <10% in central tendency and upper percentile URFs, regardless of the case evaluated. Independent draws of PBPK inputs resulted in the slightly higher URFs. Results were also comparable to corresponding values from the previously reported deterministic mouse PBPK and dose-response modeling approach that used LED(10)s to derive potency factors. This finding indicated that the adjustment from ED(10) to LED(10) in the deterministic approach for DCM compensated for variability resulting from probabilistic PBPK and dose-response modeling in the mouse. Finally, results show a similar degree of variability in DCM risk estimates from a number of different sources including the current effort even though these estimates were developed using very different techniques. Given the variety of different approaches involved, 95th percentile-to-mean risk estimate ratios of 2.1-4.1 represent reasonable bounds on variability estimates regarding probabilistic assessments of DCM.


Asunto(s)
Cloruro de Metileno/toxicidad , Modelos Biológicos , Modelos Estadísticos , Animales , Teorema de Bayes , Distribución Binomial , Relación Dosis-Respuesta a Droga , Sustancias Peligrosas/farmacocinética , Sustancias Peligrosas/toxicidad , Humanos , Análisis por Apareamiento , Cloruro de Metileno/farmacocinética , Ratones , Método de Montecarlo , Reproducibilidad de los Resultados , Medición de Riesgo/métodos , Factores de Riesgo , Solventes/farmacocinética , Solventes/toxicidad
13.
Risk Anal ; 26(4): 1059-71, 2006 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16948697

RESUMEN

We examined the relation between cancer mortality and time-dependent cumulative exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) estimated from a concentration- and age-dependent kinetic model of elimination, and we estimated incremental cancer risks at age 75. Data from the National Institute for Occupational Safety and Health study of 3,538 workers with occupational exposure to TCDD were analyzed using standardized mortality ratios and Cox regression procedures. Analyses adjusted for potential confounding by age, year of birth, and race and considered exposure lag periods of 0, 10, or 15 years. Other potential confounders including smoking and other occupational exposures were evaluated indirectly. To explore the influence of extreme values of cumulative TCDD ppt-years, we restricted the analysis to observations with exposure below the 95th percentile or used logarithmic (ln) transformed exposure values. We applied penalized smoothing splines to examine variation in the exposure-response relation across the exposure range. TCDD was not statistically significantly associated with cancer mortality using the full data set, regardless of the lag period. When we restricted the analysis to observations with exposure below the 95th percentile, TCDD was associated positively with cancer mortality, particularly when a 15-year lag was applied (untransformed exposure data: regression coefficient , standard error (s.e.) = 1.4 x 10(-6), p < 0.05; ln-transformed exposure data: , s.e. = 2.9 x 10(-2), p < 0.05). The estimated incremental lifetime risk of mortality at age 75 from all cancers was about 6 to more than 10 times lower than previous estimates derived from this cohort using exposure models that did not consider the age and concentration dependence of TCDD elimination.


Asunto(s)
Dibenzodioxinas Policloradas/administración & dosificación , Dibenzodioxinas Policloradas/toxicidad , Anciano , Industria Química , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Contaminantes Ambientales/administración & dosificación , Contaminantes Ambientales/toxicidad , Estudios de Seguimiento , Humanos , Masculino , Modelos Biológicos , Neoplasias/inducido químicamente , Neoplasias/mortalidad , Exposición Profesional , Modelos de Riesgos Proporcionales , Medición de Riesgo , Estados Unidos/epidemiología
14.
Toxicol Sci ; 91(1): 20-8, 2006 May.
Artículo en Inglés | MEDLINE | ID: mdl-16507920

RESUMEN

The U.S. Environmental Protection Agency (U.S. EPA) classifies dichloromethane (DCM) as a "probable human carcinogen," based upon its risk assessment conducted in the late 1980s (http://www.epa.gov/iris/subst/0070.htm). Since that time, cancer risk-assessment practices have evolved, leading to improved scientifically based methods for estimating risk and for illuminating as well as reducing residual uncertainties. A new physiologically based pharmacokinetic (PBPK) model has been developed, using data from human volunteers exposed to low DCM levels, that provides new information on the human to human variability in DCM metabolism and elimination (L. M. Sweeney et al., 2004, Toxicol. Lett. 154, 201-216). This information, along with data from other published human studies, has been used to develop a new cancer risk estimation model utilizing probabilistic methodology similar to that employed recently by U.S. EPA for other chemicals (ENVIRON Health Sciences Institute, 2005, Development of population cancer risk estimates for environmental exposure to dichloromethane using a physiologically based pharmacokinetic model. Final Report to Eastman Kodak Company). This article summarizes the deliberations of a scientific peer-review panel convened on 3 and 4 May 2005 at the CIIT Centers for Health Research in Research Triangle Park, North Carolina, to review the "state of the science" for DCM and to critically evaluate the new information for its utility in assessing potential human cancer risks from DCM exposure. The panel (Melvin E Andersen, CIIT Centers for Health Research, Research Triangle Park, NC 27709; A. John Bailer, Miami University, Scripps Gerontology Center, Oxford, OH 45056; Kenneth S. Crump, ENVIRON Health Sciences Institute, Ruston, LA 71270; Clifford R. Elcombe, University of Dundee, Biomedical Research Centre, Dundee DD1 9SY, United Kingdom; Linda S. Erdreich, Exponent, 420 Lexington Avenue, Suite 1740, New York, NY 10170; Jeffery W. Fisher, University of Georgia, Department of Environmental Health Science, Athens, GA 30602; David Gaylor, Gaylor and Associates, LLC, Eureka Springs, AR 72631; F Peter Guengerich, Vanderbilt University, Department of Biochemistry, Nashville, TN 37232; Kenneth Mundt, ENVIRON Health Sciences Institute, Amherst, MA 01004; Lorenz R Rhomberg, Gradient Corporation, Cambridge, MA 021138; Charles Timchalk, Pacific Northwest National Laboratory, Richland, WA 99352), chaired by M.E.A., was composed of experts in xenobiotic metabolism and carcinogenic mechanisms, PBPK modeling, epidemiology, biostatistics, and quantitative risk assessment. Observers included representatives from U.S. EPA, CIIT, and Eastman Kodak Company (Kodak), as well as several consultants to Kodak. The workshop was organized and sponsored by Kodak, which employs DCM as a solvent in the production of imaging materials. Overall, the panel concluded that the new models for DCM risk assessment were scientifically and technically sound and represented an advance over those employed in past assessments.


Asunto(s)
Carcinógenos/toxicidad , Cloruro de Metileno/toxicidad , Humanos , Farmacocinética , Probabilidad , Medición de Riesgo
15.
Toxicol Sci ; 91(1): 275-85, 2006 May.
Artículo en Inglés | MEDLINE | ID: mdl-16455694

RESUMEN

The recent National Toxicology Program (NTP) cancer bioassays for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) permit a reevaluation of the current TEF value of 4-PeCDF. The data also allow for the derivation of relative potency factors (RPFs) for cancer, which are based not only on administered dose but also on potentially more informative dose metrics, such as liver concentration, area under the liver concentration curve, and lifetime average body burden. Our analyses of these data indicate that chi-squared tests of observed versus predicted liver tumor incidence for 4-PeCDF reject the current TEF value of 0.5 value as too high. 4-PeCDF RPFs were derived using estimation methods that either did or did not assume parallelism of the 4-PeCDF and TCDD dose-response curves. The resulting parallelism-based RPFs for administered dose, liver concentration at terminal sacrifice, liver concentration AUC, and lifetime average body burden are 0.26, 0.014, 0.021, and 0.036, respectively. The administered dose RPF estimate is approximately one-half the current TEF value of 0.5. However, the use of administered dose fails to take into account pharmacokinetic differences between congeners and the generally acknowledged belief that body burden or some other measure of cumulative dose is more appropriate for estimating the health risk posed by persistent chemicals. The other three dose metrics do account for these important factors, and the corresponding RPFs are at least 10-fold lower than the current TEF for 4-PeCDF. In summary, our analyses support an administered dose TEF no greater than 0.25 and one in the 0.05-0.1 range for internal dose metrics such as lifetime average liver concentration or body burden.


Asunto(s)
Benzofuranos/toxicidad , Neoplasias Hepáticas/inducido químicamente , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Humanos , Método de Montecarlo , Células Tumorales Cultivadas
16.
Risk Anal ; 25(4): 945-56, 2005 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16268942

RESUMEN

Recent studies demonstrating a concentration dependence of elimination of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suggest that previous estimates of exposure for occupationally exposed cohorts may have underestimated actual exposure, resulting in a potential overestimate of the carcinogenic potency of TCDD in humans based on the mortality data for these cohorts. Using a database on U.S. chemical manufacturing workers potentially exposed to TCDD compiled by the National Institute for Occupational Safety and Health (NIOSH), we evaluated the impact of using a concentration- and age-dependent elimination model (CADM) (Aylward et al., 2005) on estimates of serum lipid area under the curve (AUC) for the NIOSH cohort. These data were used previously by Steenland et al. (2001) in combination with a first-order elimination model with an 8.7-year half-life to estimate cumulative serum lipid concentration (equivalent to AUC) for these workers for use in cancer dose-response assessment. Serum lipid TCDD measurements taken in 1988 for a subset of the cohort were combined with the NIOSH job exposure matrix and work histories to estimate dose rates per unit of exposure score. We evaluated the effect of choices in regression model (regression on untransformed vs. ln-transformed data and inclusion of a nonzero regression intercept) as well as the impact of choices of elimination models and parameters on estimated AUCs for the cohort. Central estimates for dose rate parameters derived from the serum-sampled subcohort were applied with the elimination models to time-specific exposure scores for the entire cohort to generate AUC estimates for all cohort members. Use of the CADM resulted in improved model fits to the serum sampling data compared to the first-order models. Dose rates varied by a factor of 50 among different combinations of elimination model, parameter sets, and regression models. Use of a CADM results in increases of up to five-fold in AUC estimates for the more highly exposed members of the cohort compared to estimates obtained using the first-order model with 8.7-year half-life. This degree of variation in the AUC estimates for this cohort would affect substantially the cancer potency estimates derived from the mortality data from this cohort. Such variability and uncertainty in the reconstructed serum lipid AUC estimates for this cohort, depending on elimination model, parameter set, and regression model, have not been described previously and are critical components in evaluating the dose-response data from the occupationally exposed populations.


Asunto(s)
Dibenzodioxinas Policloradas/toxicidad , Adulto , Factores de Edad , Anciano , Industria Química , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Humanos , Persona de Mediana Edad , Modelos Estadísticos , Exposición Profesional , Dibenzodioxinas Policloradas/administración & dosificación , Dibenzodioxinas Policloradas/sangre , Análisis de Regresión , Estados Unidos , United States Occupational Safety and Health Administration
17.
Regul Toxicol Pharmacol ; 43(2): 150-67, 2005 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-16129533

RESUMEN

Inhibition of red blood cell (RBC) cholinesterase is a consistent and sensitive indicator of exposure to dichlorvos (DDVP). Absent human data, default 10-fold adjustment factors for potential interspecies and intraspecies sensitivity differences would be used in developing a reference dose from the no observed effect levels for this endpoint obtained in toxicological assessments of laboratory animals. However, many studies of the cholinesterase-inhibiting effects associated with DDVP exposure have been conducted in humans, including healthy male volunteers, other healthy subpopulations, and diverse clinical subpopulations. Indeed, ample human data exist to permit a data-based assessment of potential interspecies sensitivity differences in RBC cholinesterase inhibition associated with DDVP exposure. In aggregate, these data demonstrate that the DDVP doses producing inhibition in humans are virtually identical to those eliciting the same levels of inhibition in laboratory rats, mice, monkeys, and dogs. Thus, healthy humans appear to be no more sensitive than laboratory animals to DDVP's effects on RBC cholinesterase, and an interspecies uncertainty factor of 1 is appropriate and scientifically warranted for use in DDVP risk assessments.


Asunto(s)
Inhibidores de la Colinesterasa/farmacología , Diclorvos/farmacología , Eritrocitos/enzimología , Algoritmos , Animales , Peso Corporal/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacocinética , Diclorvos/farmacocinética , Perros , Relación Dosis-Respuesta a Droga , Eritrocitos/efectos de los fármacos , Femenino , Haplorrinos , Humanos , Exposición por Inhalación , Masculino , Embarazo , Ratas , Especificidad de la Especie
19.
Risk Anal ; 24(3): 587-601, 2004 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15209932

RESUMEN

The extensive data from the Blair et al.((1)) epidemiology study of occupational acrylonitrile exposure among 25460 workers in eight plants in the United States provide an excellent opportunity to update quantitative risk assessments for this widely used commodity chemical. We employ the semiparametric Cox relative risk (RR) regression model with a cumulative exposure metric to model cause-specific mortality from lung cancer and all other causes. The separately estimated cause-specific cumulative hazards are then combined to provide an overall estimate of age-specific mortality risk. Age-specific estimates of the additional risk of lung cancer mortality associated with several plausible occupational exposure scenarios are obtained. For age 70, these estimates are all markedly lower than those generated with the cancer potency estimate provided in the USEPA acrylonitrile risk assessment.((2)) This result is consistent with the failure of recent occupational studies to confirm elevated lung cancer mortality among acrylonitrile-exposed workers as was originally reported by O'Berg,((3)) and it calls attention to the importance of using high-quality epidemiology data in the risk assessment process.


Asunto(s)
Acrilonitrilo/efectos adversos , Exposición Profesional , Adulto , Anciano , Anciano de 80 o más Años , Métodos Epidemiológicos , Humanos , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Enfermedades Profesionales/mortalidad , Modelos de Riesgos Proporcionales , Medición de Riesgo , Estados Unidos/epidemiología
20.
Regul Toxicol Pharmacol ; 38(2): 224-31, 2003 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-14550762

RESUMEN

A biologically based approach was taken to developing an inhalation Reference Concentration (RfC) for methanol, a high production volume chemical with many commercial applications, including use as an alternative fuel for motor vehicles and as a hydrogen source for fuel cells. Benchmark Dose methodology was applied to the most sensitive toxic endpoint for assessing potential health risks in humans, cervical rib malformation data obtained using CD-1 mice. The concentration of methanol in circulating blood was employed as the dose metric, and the maximum likelihood estimate of the blood methanol increment causing a 10% extra risk of these malformations, was 215.4 mg/L, with a lower 95% confidence bound of 97.4 mg/L. A "Reference Increment" for blood methanol was then determined by dividing this value by a 3-fold factor for residual pharmacodynamic uncertainty between species and a 10-fold factor for interindividual variation in human sensitivity to methanol. The resulting Reference Increment in blood methanol was then converted to an equivalent inhalation Reference Concentration with a physiologically based pharmacokinetic model evaluated for continuous exposure conditions. The resulting maximum likelihood estimate for the inhalation RfC was 298 mg/m3, with a 95% lower confidence bound of 135 mg/m3.


Asunto(s)
Contaminantes Ambientales/farmacocinética , Contaminantes Ambientales/toxicidad , Metanol/farmacocinética , Metanol/toxicidad , Anomalías Inducidas por Medicamentos/etiología , Administración por Inhalación , Animales , Contaminantes Ambientales/administración & dosificación , Femenino , Humanos , Intercambio Materno-Fetal , Metanol/administración & dosificación , Ratones , Modelos Animales , Embarazo , Valores de Referencia , Medición de Riesgo , Especificidad de la Especie
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