The human relevant potency threshold: Reducing uncertainty by human calibration of cumulative risk assessments

Borgert, Cristopher J.; Sargent, Edward V.; Casella, George; Dietrich, Daniel R.; McCarty, L.S.; Golden, Richard M.

doi:10.1016/j.yrtph.2011.10.012

Cited by 50 publications

(35 citation statements)

References 82 publications

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“…Interaction depends principally upon affinity, which is a term referring to the strength of interaction between two molecules. The affinity of a ligand for a specific receptor determines its residence time of association, a parameter often quantified by the dissociation constant [36]. Generally, the higher is the affinity the longer is the residence time.…”

Section: Discussionmentioning

confidence: 99%

A Computational Approach to Evaluate the Androgenic Affinity of Iprodione, Procymidone, Vinclozolin and Their Metabolites

et al. 2014

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Our research is aimed at devising and assessing a computational approach to evaluate the affinity of endocrine active substances (EASs) and their metabolites towards the ligand binding domain (LBD) of the androgen receptor (AR) in three distantly related species: human, rat, and zebrafish. We computed the affinity for all the selected molecules following a computational approach based on molecular modelling and docking. Three different classes of molecules with well-known endocrine activity (iprodione, procymidone, vinclozolin, and a selection of their metabolites) were evaluated. Our approach was demonstrated useful as the first step of chemical safety evaluation since ligand-target interaction is a necessary condition for exerting any biological effect. Moreover, a different sensitivity concerning AR LBD was computed for the tested species (rat being the least sensitive of the three). This evidence suggests that, in order not to over−/under-estimate the risks connected with the use of a chemical entity, further in vitro and/or in vivo tests should be carried out only after an accurate evaluation of the most suitable cellular system or animal species. The introduction of in silico approaches to evaluate hazard can accelerate discovery and innovation with a lower economic effort than with a fully wet strategy.

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Section: Discussionmentioning

confidence: 99%

A Computational Approach to Evaluate the Androgenic Affinity of Iprodione, Procymidone, Vinclozolin and Their Metabolites

et al. 2014

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“…Potency has long been discussed as a potential criterion for evaluation of EDs (e.g. Borgert et al, 2012;Sharpe, 2010). Application of a weight of evidence decision matrix has been suggested for the toxicological assessment of EDs by a EU report (Kortenkamp et al, 2012).…”

Section: Additional Elements Of Hazard Characterisationmentioning

confidence: 99%

Assessment of three approaches for regulatory decision making on pesticides with endocrine disrupting properties

Marx‐Stoelting

Niemann

Ritz

et al. 2014

Regulatory Toxicology and Pharmacology

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Recent EU legislation has introduced endocrine disrupting properties as a hazard-based "cut-off" criterion for the approval of active substances as pesticides and biocides. Currently, no specific science-based approach for the assessment of substances with endocrine disrupting properties has been agreed upon, although this new legislation provides interim criteria based on classification and labelling. Different proposals for decision making on potential endocrine disrupting properties in human health risk assessment have been developed by the German Federal Institute for Risk Assessment (BfR) and other regulatory bodies. All these frameworks, although differing with regard to hazard characterisation, include a toxicological assessment of adversity of the effects, the evaluation of underlying modes/mechanisms of action in animals and considerations concerning the relevance of effects to humans. Three options for regulatory decision making were tested upon 39 pesticides for their applicability and to analyze their potential impact on the regulatory status of active substances that are currently approved for use in Europe: Option 1, based purely on hazard identification (adversity, mode of action, and the plausibility that both are related); Option 2, based on hazard identification and additional elements of hazard characterisation (severity and potency); Option 3, based on the interim criteria laid down in the recent EU pesticides legislation. Additionally, the data analysed in this study were used to address the questions, which parts of the endocrine system were affected, which studies were the most sensitive and whether no observed adverse effect levels were observed for substance with ED properties. The results of this exercise represent preliminary categorisations and must not be used as a basis for definitive regulatory decisions. They demonstrate that a combination of criteria for hazard identification with additional criteria of hazard characterisation allows prioritising and differentiating between substances with regard to their regulatory concern. It is proposed to integrate these elements into a decision matrix to be used within a weight of evidence approach for the toxicological categorisation of relevant endocrine disruptors and to consider all parts of the endocrine system for regulatory decision making on endocrine disruption.

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“…The risk assessment calculation used is based on the hazard index approach. A more accurate determination of the risk of these mixtures could be calculated by a combined approach of HI, CA, and IA methods, depending on the nature of the interacting pair or the Human Relevant Potency Threshold (HRPT) method (Borgert et al 2012). Another human health risk assessment recently published, also used screening methods, found no risk from mixtures in Dutch surface water but used different methods of assessment and did not examine drug-drug interactions (de Jongh et al 2012).…”

Section: Resultsmentioning

confidence: 99%

The Cumulative Risk to Human Health of Pharmaceuticals in New Jersey Surface Water

Roden

Sargent

DiFerdinando

et al. 2014

Human and Ecological Risk Assessment: An International Journal

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Surface water in New Jersey is used by many residential drinking water facilities. Like many water sources it is contaminated by upstream industrial and residential sources, including pharmaceutical residues. This research examines the concentrations of 18 pharmaceuticals in 30 New Jersey locations, their acceptable daily exposures (ADE), and potential drug-drug interactions (DDI). The surface water data was provided by the U.S. Geological Survey (USGS). ADEs for human health were set for each pharmaceutical in the study. The pharmaceuticals were evaluated for known adverse health interactions and their potential health impact. These factors were brought together using a cumulative hazard index (HI) risk assessment calculation to assess the overall risk of pharmaceuticals in NJ surface water to human health. When examining the potential for DDI in this assessment, the risk increased but not appreciably. The HI for the sample locations ranged from <0.00001 to 0.01 with the DDI adding less than 1.2× increase to the overall risk. The calculated risk of these mixtures was also increased to an extreme DDI of 7 times per interaction. A noticeable increase in the calculated risk was seen, but in no cases did it reach a level of concern.

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The human relevant potency threshold: Reducing uncertainty by human calibration of cumulative risk assessments

Cited by 50 publications

References 82 publications

A Computational Approach to Evaluate the Androgenic Affinity of Iprodione, Procymidone, Vinclozolin and Their Metabolites

A Computational Approach to Evaluate the Androgenic Affinity of Iprodione, Procymidone, Vinclozolin and Their Metabolites

Assessment of three approaches for regulatory decision making on pesticides with endocrine disrupting properties

The Cumulative Risk to Human Health of Pharmaceuticals in New Jersey Surface Water

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