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Using 21st Century Science to Improve Risk-Related Evaluations (2017) / Chapter Skim
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Appendix D: Case Study on Assessment of New Chemistries
Pages 171-178

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From page 171...
... Acyl glucuronides have been implicated -- be ingested by people. In addition, contact with skin dur- although it is not definitively proved -- as a cause of ading the regular handling of the product is a possible route verse effects in humans because they form protein adducts of human exposure.
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From page 172...
... Here, the chemical similarity score is a measure of the similarity, in structure and properties, of a predicted chemical to chemicals in the training dataset on the basis of a nearest-neighbors approach (Brown et al.
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From page 173...
... Inhibitors of COX1 have been linked to causing ulceration and bleed- Diclofenac is shown to increase the activity of the ing in the gastrointestinal tract as a result of suppressing pregnane X receptor (PXR)
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From page 174...
... , and it is a transcriptional regulator of the cyto- comparisons, and knowledge of structural alerts, a key chrome P450 gene CYP3A4, a major metabolizing en- safety concern about all three chemicals would be liver zyme for many drugs that is highly expressed in the liver. injury through the formation of reactive acyl glucuronides Both diclofenac and ibuprofen activate the peroxi- or acyl coenzyme A conjugates that would cause tissue some proliferator–activated receptor gamma (PPAR-γ)
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From page 175...
... For the sake of illustration, the committee toxicokinetic model that considers primary routes of ex- assumes an adult human in a single room, although inposure and intake (dermal, ingestion, and inhalation) and fants and children have greater breathing rates relative to routes of elimination (for example, exhalation, renal ex- body weight; the evaluative model requires the following cretion, biotransformation, egestion, and desquamation)
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From page 176...
... considered tolerable in an environmental or occupational To put the exposure estimates in Table D-3 into con- risk assessment in which long-term, low-level exposures text, the typical over-the-counter medicines that contain of a broad population demographic have to be considered. ibuprofen recommend an oral dose of 200–400 mg ev- Similarly, conclusions cannot be drawn at this time about ery 4 hours with a maximum dose of 1,200 mg in any whether the estimated doses would ensure the protection 24-hour period for persons over 12 years old.3 However, of the most sensitive group -- pregnant women.
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From page 177...
... 2003. The nuclear pregnane X receptor regulates Baba, A., and T
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From page 178...
... 2005. Insight into hepatotoxicity: The trogli cal screening and prioritization using exposure models tazone experience.
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Key Terms

  • acyl glucuronide
  • exposure models
  • bioseek platform
  • low similarity
  • indoor environment

  • monocyte chemotactic
  • vitro bioactivity
  • pregnane x
  • oral dose
  • acyl glucuronides

  • liver injury
  • x receptor
  • adverse events
  • chemical similarity
  • cin vitro

  • human exposure
  • charged species
  • ibuprofen decreases
  • exposure pathways
  • neutral species

  • molar mass
  • daily oral
  • dermal permeation
  • maximum recommended
  • cin vivo

  • assay activity
  • bioactivity data
  • pathways include
  • partition coefficient
  • chemical structures


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