Conversion Factors Estimating Indicative Chronic No-Observed-Adverse-Effect Levels from Short-Term Toxicity Data

Kramer, Hester; Ham, Woojin; Slob, Wout; Pieters, Moniek N.

doi:10.1006/rtph.1996.0050

Cited by 57 publications

(17 citation statements)

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“…Previous analyses have evaluated ratios of NOAELs for chronic (1-2 years) versus subacute (3-6 weeks) and subchronic (10-26 weeks) exposures to animals (Kramer et al, 1996;Pieters et al, 1998). Phase 1 clinical trials (exposure 30 days) are more representative of a subacute exposure.…”

Section: Discussionmentioning

confidence: 99%

Application of the threshold of toxicological concern concept when applied to pharmaceutical manufacturing operations intended for short-term clinical trials

Bercu

Dolan

2013

Regulatory Toxicology and Pharmacology

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Section: Discussionmentioning

confidence: 99%

Application of the threshold of toxicological concern concept when applied to pharmaceutical manufacturing operations intended for short-term clinical trials

Bercu

Dolan

2013

Regulatory Toxicology and Pharmacology

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“…Indeed, the roots of the problem (measurement error and censoring) are fundamental and likely to have broader implications. They are likely to a®ect most other empirical extrapolation approaches, including`non-linear' analyses of ratios [38], regression studies extending beyond pair-wise comparisons [39,40], and other studies exploring relationships between alternative toxicity estimates [41,42,43,44,45]. They also have implications for studies of optimal design and studies comparing the relative merits of alternative toxicity measures (e.g., BMD versus NOAEL).…”

Section: Discussionmentioning

confidence: 99%

“…Because the roots of the problem (measurement error and censoring) are fundamental, the implications may be even broader. To investigate the situation, we plan to look at other empirical extrapolation approaches, including regression studies, that extend beyond pairwise comparisons, (37,38) studies that explore the relationships between alternative toxicity estimates, (39)(40)(41)(42)(43) and analyses of ratios that generalize beyond strict proportionality. (44) Generalizability to toxicity estimates drawn from continuous or categorical data is another topic for future research.…”

Section: Generalizabilitymentioning

confidence: 99%

Limitations to Empirical Extrapolation Studies: The Case of BMD Ratios

et al. 2001

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Extrapolation relationships are of keen interest to chemical risk assessment where they play a prominent role in translating experimentally derived (usually in animals) toxicity estimates into estimates more relevant to human populations. A standard approach for characterizing each extrapolation relies on ratios of pre-existing toxicity estimates.Applications of this \ratio approach" have overlooked several sources of error. We examine the case of ratios of benchmark doses (BMDs), and try to better characterize their informativeness by modeling the process by which they are generated in practice. Both closed form and simulation-based models of this \data-generating process" (DGP) are developed, paying special attention to the in°uence of experimental design. Our results show signi¯cant limits to informativeness, and revealing dependencies. The imprecision and bias of the ratio approach can no longer be ignored. We recommend bootstrap techniques, but they alone can only gauge imprecision. Proper characterizations of informativeness require more complicated techniques. Other recommendations are provided for better estimating and/or mitigating the errors. This analysis has implications that extend beyond the ratio approach to any empirical extrapolation study (involving quantal data). Such insights demonstrate the bene¯ts of understanding the DGP and the advantages of using the notion of calibration in better characterizing informativeness.

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“…8 correspond to the few data for which ED 50 values are directly available, confirming this correlation approach, since these data fall within the range of the larger set and since the extrapolation ratio of 15 is not significantly different from 26. This ratio of LD 50 / ED 50 =26 differs by less than a factor 3 from the value of 68 obtained by combining the LD 50 acute /NOAEL chronic ratio of 267 from Kramer et al (1996) with an allometric factor for rat to human of 4.1 and the NOEL/ED 50 lifetime ratio of 9× 1.79 from Huijbregts et al (2005). Note that for the noncancer human endpoint, chemicals with high toxicity often correspond to effects on the central nervous system and developmental/reproductive effects, while the less toxic ones are more often associated to irritation and vomiting (Table S4, supporting information).…”

Section: Acute-to-chronic Extrapolationmentioning

confidence: 92%

USEtox human exposure and toxicity factors for comparative assessment of toxic emissions in life cycle analysis: sensitivity to key chemical properties

Rosenbaum

Huijbregts

Henderson

et al. 2011

Int J Life Cycle Assess

197

179

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Purpose The aim of this paper is to provide science-based consensus and guidance for health effects modelling in comparative assessments based on human exposure and toxicity. This aim is achieved by (a) describing the USEtox™ exposure and toxicity models representing consensus and recommended modelling practice, (b) identifying key mechanisms influencing human exposure and toxicity effects of chemical emissions, (c) extending substance coverage. Methods The methods section of this paper contains a detailed documentation of both the human exposure and toxic effects models of USEtox™, to determine impacts on human health per kilogram substance emitted in different compartments. These are considered as scientific consensus and therefore recommended practice for comparative toxic impact assessment. The framework of the exposure model is described in details including the modelling of each exposure pathway considered (i.e. inhalation through air, ingestion through (a) drinking water, (b) agricultural produce, (c) meat and milk, and (d) fish). The calculation of human health effect factors for cancer and non-cancer effects via ingestion and inhalation exposure respectively is described. This section also includes discussions regarding parameterisation and estimation of input data needed, including route-to-route and acute-to-chronic extrapolations. Results and discussion For most chemicals in USEtox™, inhalation, above-ground agricultural produce, and fish are the important exposure pathways with key driving factors being Electronic supplementary material The online version of this article (

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Conversion Factors Estimating Indicative Chronic No-Observed-Adverse-Effect Levels from Short-Term Toxicity Data

Cited by 57 publications

References 0 publications

Application of the threshold of toxicological concern concept when applied to pharmaceutical manufacturing operations intended for short-term clinical trials

Application of the threshold of toxicological concern concept when applied to pharmaceutical manufacturing operations intended for short-term clinical trials

Limitations to Empirical Extrapolation Studies: The Case of BMD Ratios

USEtox human exposure and toxicity factors for comparative assessment of toxic emissions in life cycle analysis: sensitivity to key chemical properties

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