Requirements for a Biologically Realistic Cancer Risk Assessment for Inorganic Arsenic

Clewell, Harvey J.; Gentry, P. Robinan; Barton, Hugh A.; Shipp, Annette M.; Yager, Janice W.; Andersen, Melvin E.

doi:10.1080/109158199225701

Cited by 24 publications

(14 citation statements)

References 125 publications

(143 reference statements)

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“…Both of these endpoints have been proposed as pivotal in assessing potential nonlinearities in the noncancer and cancer responses for arsenic. The threshold for carcinogenic effects has been proposed to be roughly an order of magnitude below the concentrations at which tumors are observed [Clewell, 2001;Snow et al, 2005]. The reversal of genomic responses in the current analysis at concentrations below 0.1 lM is consistent with this evidence.…”

Section: Discussionsupporting

confidence: 87%

“…Several modes of action for arsenic carcinogenesis have been proposed [Clewell et al, 1999;Kitchin, 2001;Schoen et al, 2004;Hughes et al, 2007;Kligerman and Tennant, 2007]; however, many of these proposed MOAs lack sufficient supporting data. In general, the proposed MOAs for inorganic arsenic carcinogenicity center on arsenic or one or more of the organoarsenical metabolites having an impact on the cell's regulatory network.…”

Section: Introductionmentioning

confidence: 97%

“…In general, the proposed MOAs for inorganic arsenic carcinogenicity center on arsenic or one or more of the organoarsenical metabolites having an impact on the cell's regulatory network. These include: induction of a reactive oxygen species (ROS) protective response [Ding et al, 2005;Kligerman and Tennant, 2007], enhancement/suppression of DNA repair activity [Kitchin, 2001;Schoen et al, 2004;Snow et al, 2005;Klein et al, 2007], delays in cell cycle control [Clewell et al, 1999;Klein et al, 2007], activation of mitogenic responses (MAPK, VEGF, etc. ) [Tanaka-Kagawa et al, 2003], or apoptosis with restorative hyperplasia [Snow et al, 2005;Klein et al, 2007].…”

Section: Introductionmentioning

confidence: 99%

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Analysis of genomic dose‐response information on arsenic to inform key events in a mode of action for carcinogenicity

Gentry

McDonald

Sullivan

et al. 2009

Environ and Mol Mutagen

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A comprehensive literature search was conducted to identify information on gene expression changes following exposures to inorganic arsenic compounds. This information was organized by compound, exposure, dose/concentration, species, tissue, and cell type. A concentration-related hierarchy of responses was observed, beginning with changes in gene/protein expression associated with adaptive responses (e.g., preinflammatory responses, delay of apoptosis). Between 0.1 and 10 microM, additional gene/protein expression changes related to oxidative stress, proteotoxicity, inflammation, and proliferative signaling occur along with those related to DNA repair, cell cycle G2/M checkpoint control, and induction of apoptosis. At higher concentrations (10-100 microM), changes in apoptotic genes dominate. Comparisons of primary cell results with those obtained from immortalized or tumor-derived cell lines were also evaluated to determine the extent to which similar responses are observed across cell lines. Although immortalized cells appear to respond similarly to primary cells, caution must be exercised in using gene expression data from tumor-derived cell lines, where inactivation or overexpression of key genes (e.g., p53, Bcl-2) may lead to altered genomic responses. Data from acute in vivo exposures are of limited value for evaluating the dose-response for gene expression, because of the transient, variable, and uncertain nature of tissue exposure in these studies. The available in vitro gene expression data, together with information on the metabolism and protein binding of arsenic compounds, provide evidence of a mode of action for inorganic arsenic carcinogenicity involving interactions with critical proteins, such as those involved in DNA repair, overlaid against a background of chemical stress, including proteotoxicity and depletion of nonprotein sulfhydryls. The inhibition of DNA repair under conditions of toxicity and proliferative pressure may compromise the ability of cells to maintain the integrity of their DNA.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Analysis of genomic dose‐response information on arsenic to inform key events in a mode of action for carcinogenicity

Gentry

McDonald

Sullivan

et al. 2009

Environ and Mol Mutagen

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“…This limit, calculated from a linear dose-response curve estimated for risk of skin cancer in Taiwan population -chronically exposed to high arsenic concentrations [13,14] -has given rise to several controversies. In fact, some evidences on the non-linear relationship exposure/carcinogenesis [15], have revealed this value as overestimated. Even today, many countries in the world employ 50 g L −1 as regional or national standard, partially due to the lack of available analytical facilities for the determination of lower quantities in routine analytical laboratories.…”

Section: Introductionmentioning

confidence: 86%

Determination of As(III) and total inorganic As in water samples using an on-line solid phase extraction and flow injection hydride generation atomic absorption spectrometry

Sigrist

Albertengo

Beldoménico

et al. 2011

Journal of Hazardous Materials

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“…Additional scientific information can be incorporated in dose-response analyses by using a combination of qualitative modeof-action information with quantitative pharmacokinetic analysis (6,19,20). This approach has begun to be incorporated into noncancer dose-response assessment in the RfC process (11).…”

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confidence: 99%

Evaluating noncancer effects of trichloroethylene: dosimetry, mode of action, and risk assessment.

Barton

Clewell

2000

Environ Health Perspect

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Alternatives for developing chronic exposure limits for noncancer effects of trichloroethylene (TCE) were evaluated. These alternatives were organized within a framework for dose-response assessment-exposure:dosimetry (pharmacokinetics):mode of action (pharmacodynamics):response. This framework provides a consistent structure within which to make scientific judgments about available information, its interpretation, and use. These judgments occur in the selection of critical studies, internal dose metrics, pharmacokinetic models, approaches for interspecies extrapolation of pharmacodynamics, and uncertainty factors. Potentially limiting end points included developmental eye malformations, liver effects, immunotoxicity, and kidney toxicity from oral exposure and neurological, liver, and kidney effects by inhalation. Each end point was evaluated quantitatively using several methods. Default analyses used the traditional no-observed adverse effect level divided by uncertainty factors and the benchmark dose divided by uncertainty factors methods. Subsequently, mode-of-action and pharmacokinetic information were incorporated. Internal dose metrics were estimated using a physiologically based pharmacokinetic (PBPK) model for TCE and its major metabolites. This approach was notably useful with neurological and kidney toxicities. The human PBPK model provided estimates of human exposure doses for the internal dose metrics. Pharmacodynamic data or default assumptions were used for interspecies extrapolation. For liver and neurological effects, humans appear no more sensitive than rodents when internal dose metrics were considered. Therefore, the interspecies uncertainty factor was reduced, illustrating that uncertainty factors are a semiquantitative approach fitting into the organizational framework. Incorporation of pharmacokinetics and pharmacodynamics can result in values that differ significantly from those obtained with the default methods. Key words: benchmark dose, chloral, developmental toxicity, dose-response assessment, kidney toxicity, liver toxicity, neurotoxicity, PBPK modeling, A consistent framework has been evolving for analyzing dose-response information that reflects relevant biological processes (6,7). Depending on the availability of information, different methods can be used within the overall exposure-dosimetry modeof-action response framework (Figure 1). All dose-response assessment methods begin with the identification of a toxic effect and then estimate acceptable exposure levels protective of human health (7-10). The default approach, in the absence of information, identifies a no-observed adverse effect level (NOAEL) or lowest-observed effect level (LOAEL) and then makes assumptions about mode of action and dosimetry embodied in standard uncertainty factors and adjustments to continuous or daily exposure (11)(12)(13)(14). An This article is part of the monograph on Trichloroethylene Toxicity.

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Requirements for a Biologically Realistic Cancer Risk Assessment for Inorganic Arsenic

Cited by 24 publications

References 125 publications

Analysis of genomic dose‐response information on arsenic to inform key events in a mode of action for carcinogenicity

Analysis of genomic dose‐response information on arsenic to inform key events in a mode of action for carcinogenicity

Determination of As(III) and total inorganic As in water samples using an on-line solid phase extraction and flow injection hydride generation atomic absorption spectrometry

Evaluating noncancer effects of trichloroethylene: dosimetry, mode of action, and risk assessment.

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